3-[4-(1-substituted-4-piperazinyl)butyl]-4-thiazolidinone compounds

ABSTRACT

There are disclosed compounds of the formula ##STR1## where n is 0 or 1; A is ##STR2## where X in each occurrence is independently hydrogen, halogen, loweralkyl hydroxy, nitro, loweralkoxy, amino, cyano, trifluoromethyl or methylthio; Y in each occurrence is independently hydrogen, halogen, loweralkyl, hydroxy, nitro, loweralkoxy, amino, cyano, trifluoromethyl or methylthio; m is 1 or 2; k is 1 or 2; R 1  and R 2  are independently hydrogen, loweralkyl, ##STR3## or aryl except that when R 1  is ##STR4## or aryl, R 2  is hydrogen, or alternatively R 1  +R 2  taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, indan or piperidine ring; R 3  and R 4  are independently hydrogen or loweralkyl, or alternatively R 3  +R 4  taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, pyrrolidine or piperidine ring, the term aryl signifying an unsubstituted phenyl group or a phenyl group substituted with 1, 2 or 3 substituents each of which being independently loweralkyl, loweralkoxy, hydroxy, halogen, loweralkythio, cyano, amino or trifluoromethyl, which are useful as antipsychotic, analgesic, anticonvulsant and anxiolytic agents.

This is a continuation application of a prior application, Ser. No.07/430,688 filed Oct. 31, 1989, now U.S. Pat. No. 4,933,453 which is acontinuation-in-part application of a prior application Ser. No.123,622, filed Nov. 20, 1987, now abandoned.

The present invention relates to compounds of the formula, ##STR5##where n is 0 or 1; A is ##STR6## where X in each occurrence isindependently hydrogen, halogen, loweralkyl, hydroxy, nitro,loweralkoxy, amino, cyano, trifluoromethyl or methylthio; Y in eachoccurrence is independently hydrogen, halogen, loweralkyl, hydroxy,nitro, loweralkoxy, amino, cyano, trifluoromethyl or methylthio; m is 1or 2; k is 1 or 2; R₁ and R₂ are independently hydrogen, loweralkyl,##STR7## or aryl except that when R₁ is ##STR8## or aryl, R₂ ishydrogen, or alternatively R₁ +R₂ taken together with the carbon atom towhich they are attached form a cyclopentane, cyclohexane, cycloheptane,pyran, thiopyran, indan or piperidine ring; R₃ and R₄ are independentlyhydrogen or loweralkyl, or alternatively R₃ +R₄ taken together with thecarbon atom to which they are attached form a cyclopentane, cyclohexane,cycloheptane, pyran, thiopyran, pyrrolidine or piperidine ring, the termaryl signifying an unsubstituted phenyl group or a phenyl groupsubstituted with 1, 2 or 3 substituents each of which beingindependently loweralkyl, loweralkoxy, hydroxy, halogen, loweralkylthio,cyano, amino or trifluoromethyl, which are useful as antipsychotic,analgesic, anticonvulsant and anxiolytic agents.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, geometrical and opticalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following general rules of terminology shall apply throughout thespecification and the appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-butyl,pentyl and hexyl.

Unless otherwise stated or indicated, the term cycloalkyl denotes analicyclic hydrocarbon group containing 3 to 7 carbon atoms.

Unless otherwise stated or indicated, the term loweralkoxy denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup having 0, 1, 2 or 3 substituents each of which being independentlyloweralkyl, loweralkoxy, halogen, loweralkylthio, cyano, amino or CF₃.

The compounds of this invention are prepared by utilizing one or more ofthe steps described below. Throughout the description of the syntheticsteps, the definitions of n, m, k, A, X, Y and R₁ through R₄ are asgiven above unless otherwise stated or indicated.

STEP A

A compound of Formula II is reacted with 1,4-dibromobutane to afford acompound of Formula III. ##STR9##

The above reaction is typically conducted in the presence of a suitablemedium such as dimethylformamide or THF and a base such as potassiumhydroxide, sodium hydroxide or sodium hydride at a temperature of about23° to 70° C.

STEP B

Compound III is reacted with a compound of Formula IV to afford acompound of Formula V. ##STR10##

The above reaction is typically conducted in the presence of a suitablemedium such as anhydrous acetonitrile, an acid scavenger such aspotassium carbonate or sodium carbonate and a small amount of potassiumiodide or sodium iodide at a temperature of about 20° to 100° C.

STEP C

Compound V is oxidized with a suitable oxidizing agent such as NaIO₄ toafford a compound of Formula VI. ##STR11##

The above reaction is typically conducted in the presence of a suitablemedium such as tetrahydrofuran and water at a temperature of about -10°to 23° C.

STEP D

Compound III is oxidized in substantially the same manner as in STEP Cto afford a compound of Formula VII. ##STR12##

STEP E

Compound VII is reacted with compound IV in substantially the samemanner as in STEP B to afford a compound of Formula VI.

    (VII)+(IV)→(VI)

STEP F

As an alternative to the foregoing scheme, one can obtain a compound ofFormula VIII where P is hydrogen, loweralkyl, loweralkoxy, hydroxy,loweralkylthio or amino by reacting a compound of Formula IX with anaromatic compound of Formula X. ##STR13##

The above reaction is typically conducted in the presence of H₂ SO₄ orp-toluenesulfonic acid at a temperature of about -10° to about 83° C.

STEP G

As an alternative to the foregoing scheme, one can obtain a compound ofFormula XI where the divalent group --R-- plus the spiro carbon ascombined constitutes a cyclopentane, cyclohexane, cycloheptane, pyran,thiopyran, indan or piperidine ring, in the following manner.

First, 4-thiazolidinone is reacted with t-butyldimethylsilyl chloride ina suitable solvent such as dichloromethane at a suitable temperaturesuch as about 20°-30° C. to afford a mixture of compounds of FormulasXII and XIII. Typically the molar ratio between compound XII andcompound XIII is about 70:30. ##STR14##

The above-mentioned mixture is reacted with lithiumbis(trimethylsilyl)amide and a compound of Formula XIV where R is asdefined above and Hal is Br or I in a suitable medium such astetrahydrofuran and at a low temperature such as -75° C. to -50° C. toafford compound XI. ##STR15##

Similarly, if one uses a mono-bromide or mono-iodide of the Formula R₅--Hal where R₅ is loweralkyl in the place of Hal--R--Hal, one can obtaina compound of Formula XV and/or XVI. In this reaction, if one desires toobtain compound XV as a predominant product, it is preferable to adjustthe molar ratio between compound IIa and lithiumbis(trimethylsilyl)amide to about 1:1, whereas if one desires to obtaincompound XVI as a predominant product, it is preferable to adjust saidmolar ratio to about 1:2, also making a judicious choice in the amountof the halide compound used in each case. The two products can easily beseparated from each other with the aid of a routine technique such aschromatography. ##STR16##

STEP H

Compound IIIa (R₁ ═R₂ ═H) is allowed to react with lithiumbis(trimethylsilyl)amide and compound XIV in substantially the samemanner as in STEP G to afford a compound of formula XVII. ##STR17##

Similarly, if one uses R₅ --Hal instead of Hal--R--Hal, one can obtain acompound of formula XVIII and/or XIX. In this reaction, if one desiresto obtain compound XVIII as a predominant product, it is preferable toadjust the molar ratio between compound IIIa and lithiumbis(trimethylsilyl)amide to about 1:1, whereas if one desires to obtaincompound XIX as a predominant product, it is preferable to adjust saidmolar ratio to about 1:2, also making a judicious choice in the amountof the halide compound used in each case. The two products can easily beseparated from each other with the aid of a routine technique such aschromatography. ##STR18##

STEP I

Compound IIIa is allowed to react with lithium bis(trimethylsilyl)amideand about three equivalents of acetone in substantially the same manneras in STEP G to afford a compound of Formula XX. ##STR19##

STEP J

Compound XX is allowed to react with dimethylaminosulfur trifluoride toafford a compound of Formula XXI. ##STR20##

The above reaction is typically conducted in a suitable solvent such asdichloromethane at a temperature of -78° to 0° C.

The compounds of the present invention having Formula I are useful asantipsychotic agents.

Antipsychotic activity is determined in the climbing mice assay bymethods similar to those described by P. Protais, et al.,Psychopharmacol., 50, 1 (1976) and B. Costall, Eur. J. Pharmacol., 50,39, (1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4" by 10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally 30 minutes prior to the apomorphine challengeat a screening dose of 10 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior                                                             Mice with:             Score                                                  ______________________________________                                        4 paws on bottom (no climbing)                                                                       0                                                      2 paws on the wall (rearing)                                                                         1                                                      4 paws on the wall (full climb)                                                                      2                                                      ______________________________________                                    

Mice consistently climbing before the injection of apomorphine arediscarded.

With full-developed apomporphine climbing, the animals are hanging ontothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually last only a fewseconds.

The climbing scores are individually totaled (maximum score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a linear regressionanalysis of some of the compounds of this invention are presented inTable 1.

                  TABLE 1                                                         ______________________________________                                                              Antipsychotic Activity                                                        (Climbing Mice                                          Compound              Assay) ED.sub.50 mg/kg ip                               ______________________________________                                        3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]-                                                           12.7                                                    butyl]-4-thiazolidinone                                                       2,2-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-                                                           21.9                                                    piperazinyl]butyl-4-thiazolidinone                                            hydrochloride hydrate                                                         3-[4-[1-(3-trifluoromethylphenyl)-4-                                                                19.3                                                    piperazinyl]butyl[-4-thiazolidinone                                           hydrochloride hemihydrate                                                     3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]-                                                           12.0                                                    butyl]-5-methyl-4-thiazolidinone oxalate                                      3-[4-[1-(2-methylphenyl)-4-piperazinyl]-                                                            13.0                                                    butyl]-4-thiazolidinone hydrochloride                                         2,2-dimethyl-3-[4-[1-(3-methylphenyl)-4-                                                            16.7                                                    piperazinyl]butyl-4-thiazolidinone                                            dihydrochloride                                                               3-[4-[1-(1,2-benzisothiazol-3-yl)-4-                                                                1.4                                                     piperazinyl]butyl-5,5-dimethyl-4-                                             thiazolidinone hydrochloride                                                  (Reference Compound)                                                          Clozapine             8.1                                                     Sulpiride             14.5                                                    ______________________________________                                    

Antipsychotic response is achieved when the compounds of this inventionare administered to a subject requiring such treatment as an effectiveoral, parenteral or intraveneous dose of from 0.01 to 50 mg/kg of bodyweight per day. A particularly preferred effective amount is about 25mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgement of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not to any extent, limit the scopeor practice of the invention.

The compounds of the present invention having Formula I are also usefulas analgesic agents due to their ability to alleviate pain in mammals.The activity of the compounds is demonstrated in the2-phenyl-1,4-benzoquinone-induced writhing test in mice, a standardassay for analgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)].Table 2 shows a result of the test of the analgesic activities of someof the compounds of this invention.

                  TABLE 2                                                         ______________________________________                                                               Analgesia Activity                                                            (Phenylquinone                                                                Writhing)                                              Compound               ED.sub.50 (mg/kg sc)                                   ______________________________________                                        2-methyl-3-[4-[1-(4-fluorophenyl)-4-                                                                 1.2                                                    piperazinyl]butyl-4-thiazolidinone                                            hydrochloride                                                                 3-[4-[1-(4-chlorophenyl)-4-piperazinyl]-                                                             2.2                                                    butyl]-4-thiazolidinone hydrochloride                                         3-[4-[1-(3-methoxyphenyl)-4-piperazinyl]-                                                            4.3                                                    butyl]-4-thiazolidinone hydrochloride                                         3-[4-[1-(2,3-dimethylphenyl)-4-piperazinyl]-                                                         2.1                                                    butyl]-4-thiazolidinone hydrochloride                                         3-[4-[1-(4-fluorophenyl)-4-piperazinyl]-                                                             2.9                                                    butyl]-4-thiazolidinone                                                       3-[4-[1-(3-methylphenyl)-4-piperazinyl]-                                                             1.0                                                    butyl]-4-thiazolidinone hydrochloride                                         3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]-                                                            13.2                                                   butyl]-1,4-dioxothiazolidine                                                  (Reference Compound)                                                          Pentazocine            1.3                                                    ______________________________________                                    

Compounds I of the present invention are also useful as anticonvulsantagents. The activity of the compounds is demonstrated in supramaximalelectroshock assay. Groups of male mice (18-30 grams) are used. Drugsare prepared using distilled water and if insoluble, a surfactant isadded. Control animals receive vehicle. Drugs are routinely administeredintraperitoneally. The dosage volume is 10 ml/kg.

The animal's eyes are placed across the output terminals of an A.C.shocker that delivers 206 volts rms for 300 milliseconds. Electrodepaste coats the animal's eyes at the point of contact with theterminals.

A compound is considered to give protection if the mouse does notexhibit extensor tonus. Protection is expressed as normalized percentinhibition relative to vehicle control. ##EQU1##

A time response is carried out using 6 animals per group. Animals aretested at 30, 60, and 120 minutes postdrug. Additional time periods aretested if indicated by previous tests.

When the peak activity time has been determined, a dose response isinitiated, using 10 animals per group at that time period. The ED₅₀ and95% confidence interval are calculated by computerized probit analysis.

Results of the anticonvulsant activities of some of the compounds ofthis invention are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        ANTICONVULSANT ACTIVITY                                                                             Supramaximal                                                                  Electroshock                                            Compound              ED.sub.50, mg/kg, ip                                    ______________________________________                                        5-phenyl-3-[4-[1-(3-trifluoromethylphenyl)-                                                         14.4                                                    4-piperazinyl]butyl-4-thiazolidinone                                          oxalate                                                                       5,5-dimethyl-3-[4-[1-(3-trifluoromethyl-                                                            37.3                                                    phenyl]-4-piperazinyl]butyl]-4-                                               thiazolidinone hydrochloride                                                  (Reference Compound)                                                          Chlordiazepoxide      8.0                                                     ______________________________________                                    

Compounds of the present invention are also useful as anxiolytic agents.The activity of the compounds is demonstrated in Fixed-Ratio (FR)Conflict Paradigm in Rats.

This testing paradigm is used to reveal possible "antianxiety" effectsof compounds. The fixed-ratio (FR) conflict paradigm directly testsdrug-induced reduction in anxiety. The method is described below.

METHOD

The FR conflict paradigm is as described by Davidson and Cook, "Effectsof combined treatment with trifluoroperazine HCl and amobarbital onpunished behavior in rats", Psychopharmacologia, Volume 15, 159-168(1969). Male rats are used as test subjects. They are housedindividually and food and water are available ad libitum until they are300 to 400 g prior to the start of training. Subsequently, they are fooddeprived until their body weight is reduced to approximately 80% oforiginal and it is maintained at this level by a restricted food diet.

The programming and test equipment consists of Coulbourn Instrumentshockers and BRS/LVE cages within sound-attenuated environmentalenclosures. The data are recorded by a computer which also controls thefood and shock presentation. The cages are equipped with a hours light,a single lever, que lights, a liquid dipper, a speaker and a grid-floorconnected to a shocker. Sweetened condensed milk delivered by the liquiddipper serves as the positive reinforcement for all subjects.

The subjects are trained to lever press for the milk reward in twodistinct response-reward sections. In the anxiety or "conflict" segment(signaled by onset of both tone and que lights), a dipper of milk isdelivered in response to each fifth lever press (FR-5 schedule ofreinforcement). However, each fifth lever press during this period isalso accompanied by a 40-msec pulse of aversive footshock through thegrid floor. This creates a "conflict" between 1) easy access to milkreward and 2) the simultaneous presentation of a painful footshock. Thisconflict period is three minutes in duration.

During the other segment of this paradigm, the lever presses produce adipper of milk only at variable intervals of time from 8 to 60 secondswith an average reward of once/30 seconds (VI-30 sec.). No shocks areever administered during this VI phase of testing which is 4 minutes induration.

The test procedure consists of six (nonshock) VI segments wherereinforcement is available on a limited basis. Each VI period isfollowed by a three-minute FR-conflict phase when reinforcement isconstantly available but always accompanied by an aversive footshock.

The shock level is titrated for each subject to reduce the FR respondingto a total of more than 10 and less than 40 lever presses during theentire test. The rats are tested two to three days a week. Drugs areadministered on the day following a control day at criteria level. Aftertreatment, the performance is compared to the previous day's controltrial. The VI responses are used to evaluate any general debilitatingdrug effects while the FR responses are used to evaluate any antianxietyeffects as indicated by increased responding during the FR conflictperiod.

All test compounds are administered by i.p. injection or oral intubationin volumes of 1.0 cc/kg and the pretreat interval is usually one-halfhour after i.p. administration and 60 minutes after oral administration.

An antianxiety drug will increase the FR conflict responding. It shouldbe observed that the VI responding may also be increased.

The animals have different control VI and FR response rates and respondto antianxiety compounds at different doses. This individuality ofresponse prevents use of group averages and does not allow meaningfulED₅₀ calculation. In the standard screening procedure, at least threerats that have previously shown positive anxiolytic effects withstandard compounds are dosed with an experimental compound and tested.If no increase in FD responding is observed and the VI responding is notsufficiently suppressed to indicate general debilitation, then theanimals are retested the following week with a greater dose. At leaseone subject must show a significant increase in FR responding toindicate a positive drug effect. Drug's effects are expressed as FRconflict ratios (drug/control).

The results of this test for some of the compounds of this invention areshown in Table 4.

                  TABLE 4                                                         ______________________________________                                        ANXIOLYTIC ACTIVITY                                                                                    FR         (drug/                                                  dose       conflict ratios                                                                          control)                                  Compound      (mg/kg i.p.)                                                                             responses  rewards                                   ______________________________________                                        2,2-dimethyl-3-                                                                             10         2.7        3.6                                       [4-[1-(3-methyl-                                                              mercaptophenyl)-4-                                                            piperazinyl]-                                                                 butyl]-4-thiazoli-                                                            dinone dihydrochloride                                                        5,5-dimethyl-3-                                                                             20         1.8        2.2                                       [4-[1-(3-tri-                                                                 fluoromethyl-                                                                 phenyl)-4-                                                                    piperazinyl]-                                                                 butyl]-4-                                                                     thiazolidinone                                                                hydrochloride                                                                 (reference compound)                                                          Diazepam      15         4.5        6.5                                       ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsule or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 5% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweeting agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present inventions are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraactic acid; buffers such asacetates; citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral multipledose vials may be of glass or plastic.

Examples of the compounds of this invention include:

3-[4-[1-(2-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(2,3-dimethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(3-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(2-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(4-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidine;

3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidine;

3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone;

3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone;

3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone;

3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-5-methyl-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone

2,2-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-methylmercaptophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5-phenyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2-methyl-3-[4-[1-(2-pyrimidinyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(2-benzisothiazolyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(2-quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(2-quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2,2-dimethyl-3-[4-[1-(3-methylthiophenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5-phenyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone;

2-methyl-3-[4-[1-(2-pyrimidyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidinone;

3-[4-[1-(2-benzothiazolyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(2-quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone;

5,5-dimethyl-3-[4-[1-(2-quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(5-fluoro-2-pyrimidinyl)-4-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidinone;

3-[4-[1-(3-isoquinolinyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(3-isoquinolinyl)-4-piperazinyl]butyl]-1-thia-3-azaspiro-[4.4]-nonan-4-one;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro-[4.4]-nonan-4-one;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2-methyl-1-thia-3-azaspiro-[4.4]-nonan-4-one;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,2-dimethyl-1-thia-3-azaspiro-[4.4]-nonan-4-one;

3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,2-dimethyl-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,2,5,5-tetramethyl-4-thiazolidinone;

3-[3-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]propyl]-5-methyl-4-thiazolidinone;

3-[4-[1-(2-methylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(2,3-dimethylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(1-phenyl-1H-indol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-[1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(benzo[b]thiophen-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]-one;

3-[4-[1-(1-phenyl-1H-indol-3-yl)-4-piperazinyl]butyl]-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one;

3-[4-(1-benzo[b]thiophen-3-yl)-4-piperazinyl)butyl]-1-thia-3-azaspiro[4.5]decan-4-one;

3-[4-[1-(1-phenyl-1H-indol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[5.4]decan-4-one;

3-[4-[1-[1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.5]decan-4-one;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-5-butyl-4-thiazolidinone;

3-[4-[1-(2-(5-fluoropyrimidinyl))-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone;

3-[4-[1-(2-(6-fluoropyridinyl))-4-piperazinyl]butyl]-4-4-thiazolidinone;

2,5,5-trimethyl-3-[4-[1-(2-(3-cyanopyridinyl))-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(benzo[b]furan-3-yl)-4-piperazinyl]butyl]-5-ethyl-4-thiazolidinone;

3-[4-[1-(4-pyridinyl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one;

3-[4-[1-(6-fluorobenzo[b]furan-3-yl)-4-piperazinyl]butyl]-5-methyl-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[6.4]undecan-4-one;

3-[4-[1-(6-chloro-1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-5-(2-hydroxyisopropyl)-4-thiazolidinone;

3-[4-[1-(2-(3-chloropyridinyl)-4-piperazinyl]butyl]-5-(2-fluoroisopropyl)-4-thiazolidinone;

2,5,5-trimethyl-3-[4-[1-(2-(5-chlorothiophenyl))-4-piperazinyl]butyl]-4-thiazolidinone;

2-methyl-3-[4-[1-(2-(5-fluoropyrimidinyl))-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one;

2,5,5-trimethyl-3-[4-[1-(6-chloro-1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-4-thiazolidinone;

2-methyl-3-[4-[1-(1-phenyl-6-fluoro-1H-indol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one;

2,5,5-trimethyl-3-[4-[1-(6-fluorobenzo[b]thiophen-3-yl)-4-piperazinyl]butyl]-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-5-(2-hydroxyisopropyl)-4-thiazolidinone;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-spiro[1H-indene-2,5-thiazolidine]-2,3-dihydro-4-one;

3-(4-(1-[1,2-benzisothiazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4-thiazolidinone;

3-(4-(1-(6-fluorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl-5-(2-hydroxyisopropyl)-4-thiazolidinone;

3-(4-(1-(1,2-benzisothiazol-3-yl)-4-piperazinyl)butyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone;

3-(4-(1-(3-methylphenyl)-4-piperazinyl)butyl)-5,5-dimethyl-4-thiazolidinone;

3-(4-(1-(6-chlorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinone;

3-(4-(1-[1-phenyl-1H-indol-3-yl]-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinone;

3-(4-(1-(1-(4-fluorophenyl)-1H-indol-3-yl)-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinone;

3-(4-(1-[3-methylphenyl]-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinone;

3-(4-(1-(2-methoxyphenyl)-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinone;

3-(4-(1-(2-methoxyphenyl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-(benzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-one;

3-[4-[1-(1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-(1,1-dioxo-1,2-benzisothiazol-3-yl-1)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-(6-fluorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2-methyl-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-(6-chlorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-(1,2-benzisothiazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one;

3-(4-(1-[1,2-benzisothiazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan-4-one;

3-[4-[1-(6-chloro-1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.5]decan-4-one;

The following examples are presented in order to illustrate thisinvention.

EXAMPLE 1 5,5-Dimethyl-4-thiazolidinone

A solution of 4-thiazolidinone (10.0 g), t-butyldimethylsilyl chloride(16.40 g), triethylamine (20.3 mL) and CH₂ Cl₂ (250 mL) was stirred atroom temperature under nitrogen. After 15 min. the reaction mixturebecame cloudy. After 27 h, Et₂ O (200 mL) was added, the mixture wasfiltered through Al₂ O₃ and the triethylammonium chloride cake washedwith Et₂ O (350 mL). The combined filtrate was concentrated in vacuo toa cloudy oil (26.1 g). Distillation of the cloudy oil gave 19.63 g of aclear liquid, bp. 73°-75° C. at 0.30 mmHg. Spectral data showed oil tobe a 70:30 mixture of N- and O- silylated material, namely,3-t-butyldimethylsilyl-4-thiazolidinone and4-t-butyldimethylsilyloxy-3-thiazoline.

To a -45° C. solution of lithium bis(trimethylsilyl)amide (80.0 mmol)and tetrahydrofuran (80 mL) under N₂ was added a 0° C. solution preparedfrom 7.91 g of the above-mentioned 70:30 mixture between3-t-butyldimethylsilyl-4-thiazolidinone and4-t-butyldimethylsilyloxy-3-thiazoline, iodomethane (11.36 g) and THF(30 mL). The reaction mixture was stirred at -40° C. to -50° C. for 70min. TLC analysis (silica gel, 7% ethyl acetate/hexane) showed a traceof starting material, R_(f) =0.31, and a major product, R_(f) =0.50,along with material at the origin. The reaction mixture was removed fromthe cold bath and quenched with 2N HCl (120 mL). The aqueous mixture wasstirred rapidly for 1.5 h. TLC analysis (silica gel, ethyl acetate)showed a major product, R_(f) =0.45, and 4-thiazolidinone, R_(f) =0.31,after visualization with iodine. The aqueous mixture was evaporated invacuo to remove tetrahydrofuran and the resultant aqueous mixture wasextracted with dichloromethane (5×70 mL). The combined extracts werewashed with brine (150 mL), dried over Na₂ SO₄ and concentrated in vacuoto 3.88 g of a dark solid. The crude product was flash chromatographed(180 g silica gel, 10% hexane/ethyl acetate) to give 2.28 g of anoff-white solid. It was recrystallized from diethyl ether (25 ml) toyield 1.12 g of crystals, mp 105°-107° C.

ANALYSIS: Calculated for C₅ H₉ NOS: 45.77%C; 6.92%H; 10.68%N. Found:45.74%C; 6.88%H; 10.67%N.

EXAMPLE 2 1-Thia-3-azaspiro[4.4]nonane-4-one

To a -75° C. (CO₂ /isopropanol bath) mixture of lithiumbis(trimethylsilyl)amide (0.151 mol) and THF (151 mL) under nitrogen wasadded a 0° C. solution prepared from 14.95 g of a 70:30 mixture between3-t-butyldimethylsilyl-4-oxothiazolidine and4-t-butyldimethylsilyloxy-3-thiazoline (prepared as in Example 1) and1,4-dibromobutane (14.85 g) in THF (50 mL) over a period of 0.5 h. Theresultant homogeneous solution was stirred at -75° C. for 70 min. TLCanalysis (silica gel, 10% EtOAc/hexane) showed a major product, (R_(f)=0.48) and a minor product (R_(f) =0.31). The reaction mixture wasremoved from the cold bath and acidified with 2N HCl (200 mL). Theaqueous mixture was stirred rapidly for 3.5 h at room temperature,placed in vacuo to remove the tetrahydrofuran, and extracted withdichloromethane (5×75 mL). The organic extracts were dried over Na₂ SO₄and concentrated in vacuo to yield 14.2 g of an oily solid. The crudeoily product was chromatographed (Waters Prep 500, 2 silica gel columns,20% hexane/ethyl acetate) to give 2.75 g of a white solid (R_(f) =0.45).Recrystallization from diethylether/hexane yielded 1.37 g of acrystalline solid, mp 92°-94° C.

ANALYSIS: Calculated for C₇ H₁₁ NOS: 53.47%C; 7.05%H; 8.91%N. Found:53.41%C; 7.01%H; 8.88%N.

EXAMPLE 3 3-(4-Bromobutyl)-4-thiazolidinone

A mixture of 4-thiazolidinone (25 g), dimethylformamide (DMF hereafter,500 ml) and KOH (27.16 g) was stirred under N₂ at room temperature for1.5 h. To the resulting mixture was added 1,4-dibromobutane (101 ml),which rapidly caused the reaction mixture to turn milkyl white. Stirringwas continued at room temperature for 44 h. The reaction mixture waspoured into H₂ O (1000 ml) and the aqueous mixture was extracted withethyl acetate (EtOAc hereafter, 3×300 ml). The combined extracts werewashed successively with H₂ O (300 ml) and brine (300 ml), dried overNa₂ SO₄, and concentrated in vacuo to an amber oil. HPLC (highperformance liquid chromatography) of a 44.95 g aliquot yielded 7.15 gof an oil which upon distillation yielded a clear liquid, b.p. 134°-137°C./0.12 mm Hg.

ANALYSIS: Calculated for C₇ H₁₂ BrNOS: 35.30%C; 5.08%H; 5.88%N. Found:35.24%C; 5.09%H; 5.83%N.

EXAMPLE 4 3-(4-Bromobutyl)-5,5-dimethyl-4-thiazolidinone

To a -75° C. (CO₂ /isopropanol bath) mixture of lithiumbis(trimethylsilyl)amide and tetrahydrofuran (102 mL) under nitrogen wasadded a 0° C. solution consisting of 3-(4-bromobutyl)-4-thiazolidinone(11.65 g), iodomethane (20.8 g) and tetrahydrofuran (20 mL) over aperiod of 20 min. The resultant solution was stirred at -75° C. for 25min. TLC analysis (silica gel, 32% EtOAc/hexane) of a small aliquotacidified with 1N HCl showed the absence of a starting bromide and thepresence of a major product, R_(f) ≅0.41. The reaction mixture wasremoved from the cold bath and acidified with 1N HCl (200 mL). Theaqueous mixture was extracted with diethyl ether (3×175 mL). Thecombined extracts were washed with brine (200 ml), dried over Na₂ SO₄and concentrated in vacuo to an oil. The crude oil was chromatographed(Waters Prep 500, 2 silica gel columns, 30% EtOAc/hexane) to give 11.02g of an oil as the major product, R_(f) ≅0.41. A sample (2.80 g) of thiswas distilled using a short path head yielding 2.68 g of a faint yellowoil (bath temperature 90°-100° C./0.05 mm Hg).

ANALYSIS: Calculated for C₉ H₁₆ BrNOS: 40.60%C; 6.06%H; 5.26%N. Found:40.64%C; 6.12%H; 5.20%N.

EXAMPLE 5 2-Methyl-3-(4-bromobutyl)-4-thiazolidinone

To a stirred suspension of 2-methyl-4-thiazolidinone (20 g) in 500 ml ofanhydrous DMF under N₂ was added in one portion potassium hydroxide(19.1 g). Stirring was continued for 1/2 h resulting in a yellowsolution. At this time 1,4-dibromobutane (61 ml) was added in oneportion.

After 1 hour, no starting material remained as judged by TLC [silica,EtOAc]. The mixture was quenched in 600 ml of H₂ O and extractedexhaustively with EtOAc. The organic fractions were washed twice with H₂O, dried over MgSO₄ and concentrated in vacuo. HPLC of the residue,using a 3:1 hexane/EtOAc eluent, provided 16.02 g of product as an oilwhich was homogeneous by TLC [silica 2:1 hexane/EtOAc].

ANALYSIS: Calculated for C₈ H₁₄ BrNOS: 38.10%C; 5.60%H; 5.55%N. Found:37.81%C; 5.78%H; 5.39%N.

EXAMPLE 6 3-(4-Bromobutyl)-2,2-dimethyl-4-thiazolidinone

A solution of 2,2-dimethyl-4-thiazolidinone (5.00 g) in DMF (30 ml) wasadded dropwise to a suspension of NaH (0.0419 mole, previously washedwith hexane) in DMF (30 ml) under N₂. The resultant mixture was stirredfor 1 h, transferred to an addition funnel and added dropwise to asolution of 1,4-dibromobutane (18.10 g) in DMF (50 ml) over a period of40 min. The resultant solution was heated at 70° C. under N₂ for 120 hr.TLC analysis (silica gel, 10% EtOAc/CH₂ Cl₂) showed the presence of onemajor product and starting thiazolidinone. The reaction mixture wascooled to room temperature and poured into H₂ O (400 ml), and theaqueous mixture extracted with EtOAc (3×175 ml). The combined extractswere washed with H₂ O (200 ml) and brine (200 ml), dried over Na₂ SO₄,and concentrated in vacuo to an oily residue (20.44 g). The crudeproduct was purified by HPLC (4% EtOAc/CH₂ Cl₂) to yield 5.91 g of oil.Distillation in vacuo afforded 4.61 g of a faint yellowish oil, bp133°-136° C./0.70 mm Hg.

ANALYSIS: Calculated for C₉ H₁₆ BrNOS: 40.60%C; 6.06%H; 5.26%N. Found:40.63%C; 6.03%H; 5.17%N.

EXAMPLE 7 3-(4-Bromobutyl)-5-methyl-4-thiazolidinone

To 12.35 g of 5-methyl-4-thiazolidinone placed in a 500 ml round bottomflask was added 210 ml of DMF and the mixture stirred for 3.5 h. Anadditional 30 ml of DMF was added and the mixture stirred for 10 minutesand thereafter 11.8 g of KOH was added all at once. The resultantsolution was stirred for 0.5 h at room temperature and thereafter 38 mlof 1,4-dibromobutane was added rapidly. The mixture was stirred at roomtemperature overnight. After 24 hours of stirring at room temperature,the reaction mixture was poured into 600 ml of water and the resultantmixture extracted with EtOAc (2×175 ml). The combined EtOAc layers werewashed successively with water (200 ml) and brine (150 ml), dried overMgSO₄ and concentrated in vacuo to 49.68 g of oil. After removal of DMFby vacuum distillation, the residual oil was purified by flashchromotography (silica gel column) to obtain the desired product.

EXAMPLE 8 3-(4-Bromobutyl)-5-phenyl-4-thiazolidinone

To a rapidly stirred mixture of H₂ SO₄ (73 ml) and benzene (30 ml) wasadded a mixture of 3-(4-bromobutyl)-1,4-dioxothiazolidine (13.66 g,prepared from 3-(4-bromobutyl)-4-thiazolidinone by oxidation with NaIO₄conducted in substantially the same manner as in Example 17 describedlater), benzene (120 ml) and CH₂ Cl₂ (10 ml). The exothermic reactionwas cooled with an ice/water bath and stirring was continued for 50minutes, during which the mixture was gradually warmed to roomtemperature. The mixture was poured onto 750 g of ice and extracted withCH₂ Cl₂ (4×150 ml). The combined extracts were washed with 5% NaHCO₃(300 ml), H₂ O (300 ml) and brine (300 ml), dried over Na₂ SO₄, andconcentrated in vacuo to yield 15.00 g of an oil. TLC analysis (silicagel, 40% EtOAc/hexane) showed a major product with Rf=0.37. The crudeoil was purified by HPLC chromatography, whereupon the productsolidified. It (6.17 g) was recrystallized from Et₂ O to yield 2.7 g ofa crystalline solid, mp 48°-50° C.

ANALYSIS: Calculated for C₁₃ H₁₆ BrNOS: 49.68%C; 5.13%H; 4.46%N. Found:49.73%C; 5.26%H; 4.78%N.

EXAMPLE 9 3-(4-Bromobutyl)-5-(4-methoxyphenyl)-4-thiazolidinone

A mixture of p-toluenesulfonic acid monohydrate (6.56 g) and1,2-dichloroethane (100 mL) was heated to reflux using an apparatusequipped with a water separator. Approximately 70 mL of distillate wasremoved and the reddish solution was cooled to room temperature. To thissolution was added anisole (9.30 g), followed by a solution of3-(4-bromobutyl)-1,4-dioxothiazolidine (4.38 g) and 1,2-dichloroethane(60 mL) and the resultant mixture was heated to reflux (bathtemperature=120° C.). Approximately 60 mL of distillate was removed,another 30 mL of 1,2-dichloroethane was added, and the reaction allowedto reflux. Another 30 mL of distillate was removed, the reaction mixturewas cooled to ambient temperature and poured into H₂ O (60 mL). Theaqueous mixture was extracted with Et₂ O (4×40 mL) and the combinedextracts were washed with brine (70 mL), dried (Na₂ SO₄) andconcentrated in vacuo to a yellow liquid. TLC analysis (silica gel, 2%EtOAc/CH₂ Cl₂) of the liquid showed an elongated spot, R_(f) ≅0.33. Theyellow liquid was chromatographed to afford 3.70 g of oil, a mixture ofo- and p- isomers as determined by proton NMR and 1.55 g of the purep-isomer (R_(f) =0.48, silica gel, 3% EtOAc/CH₂ Cl₂). The latter wasdried at room temperature/0.1 mmHg for 100 h.

ANALYSIS: Calculated for C₁₄ H₁₈ BrNO₂ S: 48.84%C; 5.27%H; 4.07%N.Found: 48.61%C; 5.40%H; 3.97%N.

EXAMPLE 103-[4-[1-(2-Methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.10 g),1-(2-methylphenyl)piperazine (5.6 g), K₂ CO₃ (7.13 g), NaI (300 mg) andCH₃ CN (200 ml) was refluxed (oil bath temperature 95° C.) under N₂ for20 h. TLC analysis (silica gel, 20% MeOH/EtOAc) showed one major productat Rf=0.37, and a trace of starting bromide at Rf=0.67. The mixture wascooled to room temperature, EtOAc (100 ml) was added and the mixture wasfiltered. The filtrate was concentrated in vacuo to an oil which wastriturated with EtOAc to precipitate a solid. The mixture was filteredand the filtrate concentrated in vacuo to an oil. The oil waschromatographed by HPLC over silica gel and the purified oil (5.42 g)was dissolved in Et₂ O (600 ml). The salt of this amine was precipitatedby the addition of an HCl/Et₂ O solution until pH=1, yielding 5.50 g ofcrystals. The crude salt (4.00 g) was recrystallized from EtOH/EtOAc toyield 3.13 g of a crystal solid, mp 207°-209° C.

ANALYSIS: Calculated for C₁₈ H₂₇ N₃ OS.HCl: 58.44%C; 7.63%H; 11.36%N;9.58%Cl. Found: 58.35%C; 7.56%H; 11.35%N; 9.69%Cl.

EXAMPLE 113-[4-[1-(3-Methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(3-tolyl)piperazine dihydrochloride (4.23 g), K₂ CO₃ (9.40 g), NaI(200 mg) and CH₃ CN (150 ml) was heated at reflux (bath temperature 90°C.) under N₂ for 52 h. TLC analysis (silica gel, 7.5% EtOH/CH₂ Cl₂)showed some starting bromide at Rf=0.57 and a major product at Rf=0.41.The reaction mixture was cooled to room temperature, filtered, and thefiltrate concentrated in vacuo to an oil. The crude product was flashchromatographed (silica gel) to yield 3.40 g of a heavy oil. TLCanalysis (silica gel) of this showed the presence of starting bromide.The oil solidified on cooling and the resultant solid was trituratedwith Et₂ O/hexane yielding 2.48 g of solid, mp 69°-73° C. Flashchromatography (silica gel) of the crude product afforded 2.10 g of apurified solid, mp 70°-72° C. The salt of this amine was prepared inether by the addition of an HCl/Et₂ O solution. It was recrystallizedfrom EtOH/EtOAc to provide 1.55 g of white crystals, mp 201°-203° C.

ANALYSIS: Calculated for C₁₈ H₂₇ N₃ OS.HCl: 58.44%C; 7.63%H; 11.36%N.Found: 58.44%C; 7.73%H; 11.31%N.

EXAMPLE 123-[4-[1-(2,3-Dimethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (4.0 g) and1-(2,3-dimethylphenyl)piperazine hydrochloride (3.8 g) in 100 ml ofanhydrous CH₃ CN were added K₂ CO₃ (9.3 g) and NaI (200 mg). The mixturewas heated to 80° with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc and filteredagain. The solvent was removed in vacuo and the residue chromatographedon silica using 98:2 EtOAc/CH₃ OH as an eluent. Fractions containing thepure product were combined and concentrated to give 3.36 g of freeamine.

The HCl salt of this amine was precipitated from Et₂ O to provide 3.118g of product, mp 228°-230° C.

ANALYSIS: Calculated for C₁₉ H₂₉ N₃ OS.HCl: 59.43%C; 7.87%H; 10.94%N.Found: 59.34%C; 8.07%H; 10.93%N.

EXAMPLE 133-[4-[1-(2-Methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone

A suspension of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g),1-(2-methoxyphenyl)piperazine (2.43 g), anhydrous K₂ CO₃ (3 g) and NaI(200 mg) in 100 ml of anhydrous CH₃ CN was heated to reflux under N₂.After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, and the residue taken up andchromatographed (silica, EtOAc eluent) to provide 3.49 g of product as awhite solid, mp 80°-81° C.

ANALYSIS: Calculated for C₁₈ H₂₇ N₃ O₂ S: 61.86%C; 7.79%H; 12.02%N.Found: 62.07%C; 7.89%H; 11.95%N.

EXAMPLE 143-[4-[1-(3-Methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and1-(3-methoxyphenyl)piperazine dihydrochloride (3.34 g) in 100 ml ofanhydrous CH₃ CN were added K₂ CO₃ (8.7 g) and NaI (200 mg). The mixturewas heated to 80° with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The CH₃ CN was removed in vacuo and the residue was chromatographed onsilica using 98:2 EtOAc/CH₃ OH as the eluent. The fractions containingthe desired product were combined, concentrated in vacuo and taken up inanhydrous Et₂ O.

The HCl salt of the free amine was precipitated from Et₂ O, collectedand dried to provide 2.850 g of product, mp 161°-162° C.

ANALYSIS: Calculated for C₁₈ H₂₇ N₃ O₂ S.HCl: 56.02%C; 7.31%H; 10.89%N.Found: 55.66%C; 7.37%H; 10.83%N.

EXAMPLE 153-[4-[1-(4-Fluorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.01 g),1-(4-fluorophenyl)piperazine (3.35 g), K₂ CO₃ (4.64 g), NaI (150 mg) andCH₃ CN (150 ml) was heated at 100° C. (bath temperature) under N₂ for 18h. TLC analysis (silica gel, 8% MeOH/CHCl₃) showed one major product atR_(f) =0.36, and the absence of starting bromide. The reaction mixturewas cooled to room temperature and concentrated in vacuo to an oil whichwas taken up in EtOAc. The mixture was filtered to remove theprecipitate and the filtrate concentrated in vacuo to an amber oil whichsolidified under vacuum. The solid (5.86 g) was dissolved in CHCl₃ andflash chromatographed (silica gel) and thereafter recrystallized fromhexane/CH₂ Cl₂ to yield in two crops 3.93 g of white crystals, mp83°-85° C. TLC analysis showed a trace of slower moving impurity.Recrystallization from hexane/CH₂ Cl₂ afforded 3.1 g of white needleswhich were still slightly impure by TLC. The material was again flashchromatographed (silica gel) and recrystallized from hexane/CH₂ Cl₂ togive 2.67 g of pure product, mp 84°-85° C.

ANALYSIS: Calculated for C₁₇ H₂₄ N₃ OSF: 60.50%C; 7.17%H; 12.45%N.Found: 60.55%C; 7.19%H; 12.43%N.

EXAMPLE 163-[4-[1-(2-Chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.02 g),1-(2-chlorophenyl)piperazine (3.94 g), K₂ CO₃ (7.01 g), NaI (250 mg) andCH₃ CN (130 ml) was heated at 100° C. (bath temperature) for 20 hoursunder N₂. The mixture was cooled to room temperature, filtered andconcentrated in vacuo to an amber oil. The oil was triturated with EtOAcand the mixture was filtered. The filtrate was concentrated in vacuo to6.07 g of an oil residue which was flash chromatographed (silica gel) toyield 4.47 g of an oily product. The HCl salt of this amine was preparedin ether with ethereal HCl to give 3.77 g of a white solid, mp 182°-185°C. The solid was recrystallized from EtOAc (130 ml)/CH₂ Cl₂ (30 ml)yielding 3.01 g of white needles, mp 185°-187° C.

ANALYSIS: Calculated for C₁₇ H₂₄ N₃ ClOS.HCl: 52.30%C; 6.46%H; 10.76%N.Found: 52.28%C; 6.51%H; 10.64%N.

EXAMPLE 173-[4-[1-(3-Chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and1-(2-chlorophenyl)piperazine dihydrochloride (3.4 g) in 100 ml ofanhydrous CH₃ CN were added K₂ CO₃ (8.7 g) and NaI (200 mg). The mixturewas heated at 80° with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc andchromatographed on silica using EtOAc/CH₃ OH (95:5) as the eluent. Thefractions containing the product were combined and concentrated invacuo.

The HCl salt of the amine was precipitated from Et₂ O, dried andcollected to provide 2.7 g of product, mp 157°-159° C.

ANALYSIS: Calculated for C₁₇ H₂₄ ClN₃ OS.HCl: 52.30%C; 6.45%H; 10.76%N.Found: 51.93%C; 6.80%H; 10.81%N.

EXAMPLE 183-[4-[1-(4-Chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and1-(4-chlorophenyl)piperazine dihydrochloride (3.4 g) in 100 ml ofanhydrous CH₃ CN were added K₂ CO₃ (8.7 g) and KI (200 mg). The mixturewas heated to 80° with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc andchromatographed on silica using EtOAc/CH₃ OH (95:5) as the eluent. Thefractions containing the product were combined and concentrated invacuo.

The HCl salt of the amine was precipitated from Et₂ O, dried andcollected to provide 2.33 g of product, mp 186°-188° C. (dec).

ANALYSIS: Calculated for C₁₇ H₂₄ ClN₃ OS.HCl: 52.30%C; 6.45%H; 10.76%N.Found: 52.17%C; 6.51%H; 10.85%N.

EXAMPLE 193-[4-[1-(3-Trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride hemihydrate

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and1-(3-trifluoromethylphenyl)piperazine (2.91 g) in 100 ml of anhydrousCH₃ CN were added K₂ CO₃ (3.5 g) and KI (200 mg). The mixture was heatedto 80° with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc, filtered andconcentrated. The residue was chromatographed on silica using EtOAc asthe eluent, and fractions containing the product were combined andconcentrated in vacuo.

The HCl salt of this amine was precipitated from Et₂ O, dried andcollected to provide 3.7458 g of product as a hemihydrate, mp 138°-140°.

ANALYSIS: Calculated for C₁₈ H₂₄ N₃ F₃ OS.HCl.1/2H₂ O: 49.94%C; 6.05%H;9.70%N. Found: 49.85%C; 6.07%H; 9.77%N.

EXAMPLE 203-[4-[1-(2-Methoxyphenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidine

A mixture of 3-(4-bromobutyl)-1,4-dioxothiazolidine (3.37 g),1-(2-methoxyphenyl)piperazine (2.80 g), K₂ CO₃ (4.60 g), NaI (190 mg)and CH₃ CN (150 ml) was heated at reflux (bath temperature 95° C.) for24 h. TLC analysis (silica gel, 20% MeOH/CH₂ Cl₂) showed the consumptionof the starting sulfoxide and the presence of one major product withR_(f) =0.43. The mixture was cooled to room temperature, EtOAc (100 m)was added and the mixture was filtered. The filtrate was concentrated invacuo to an oil which was filtered through silica gel using 20% MeOH/CH₂Cl₂ as the eluent. The fractions containing the material with R_(f)=0.43 were concentrated in vacuo to yield 4.83 g of a foam, which wasdissolved in MeOH/CH₂ Cl₂ and flash chromatographed (silica gel) toyield 3.28 g of a crude product. Rechromatography over silica gel using50% MeOH/toluene as eluent yielded 2.98 g of an oil which solidified onstanding. The solid was dissolved in 50% MeOH/EtOAc and filtered throughsilica gel. The filtrate containing the product was concentrated toapproximately 5 ml and the oily liquid was seeded and left standing,yielding 0.91 g of a white solid, mp, 111°-113° C. The mother liquor wasconcentrated in vacuo to a solid which was recrystallized from CH₂ Cl₂/Et₂ O, yielding an additional 0.79 g of fine needles, mp, 111°-113° C.

ANALYSIS: Calculated for C₁₈ H₂₇ N₃ O₃ S: 59.15%C; 7.48%H; 11.50%N.Found: 59.02%C; 7.06%H; 11.49%N.

EXAMPLE 213-[4-[1-(4-Fluorophenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidine

To a solution of NaIO₄ (710 mg) in H₂ O (12 ml) was added a solution of3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone 1, (1.02g) in tetrahydrofuran (THF, 12 ml). The resultant mixture was stirred atroom temperature for 18 h. TLC analysis (silica gel, 30% MeOH/CHCl₃)showed a major product with R_(f) =0.33 along with a material having thesame R_(f) as 1, namely 0.79. The mixture was filtered to remove theNaIO₃. The filtrate was concentrated in vacuo, poured into H₂ O (35 ml)and extracted with CH₂ Cl₂ (4×20 ml). The combined extracts were washedwith brine (50 ml), dried through Na₂ SO₄ and concentrated to an oil.Flash chromatography over silica gel afforded 185 mg of material withR_(f) identical to 1 and 0.520 g of an oil which solidified on standing.

A second run using NaIO₄ (1.41 g), H₂ O (13 ml), 1 (2.02 g) and THF (20ml) was conducted in a similar manner yielding 0.910 g of product.

The combined products, 1.43 g, were dissolved in 50% MeOH/EtOAC andfiltered through silica gel using 50% MeOH/EtOAc as eluent. Thefractions containing the product were concentrated to approximately 8ml, seeded, and left to deposit 1.02 g of a white crystalline material,mp, 118°-119.5° C.

ANALYSIS: Calculated for C₁₇ H₂₄ N₃ O₂ FS: 57.77%C; 6.84%H; 11.89%N.Found: 57.61%C; 6.83%H; 11.83%N.

EXAMPLE 223-[4-[1-(2-Methoxyphenyl)-4-piperazinyl]butyl]-2-Methyl-4-thiazolidinone

A suspension of 2-methyl-3-(4-bromobutyl)-4-thiazolidinone (3.0 g),1-(2-methoxyphenyl)piperazine (2.3 g), anhydrous K₂ CO₃ (3.5 g) and NaI(200 mg) in 100 ml of anhydrous CH₃ CN was heated to 80° under N₂. After4 hours no starting material remained as judged by TLC. The mixture wascooled to room temperature, filtered and concentrated in vacuo. Theresidue was chromatographed on silica, using EtOAc as the eluent. Thisprovided 2.18 g of product as a clear oil which solidified in vacuo (0.1mmHg) overnight.

ANALYSIS: Calculated for C₁₉ H₂₉ N₃ O₂ S: 62.78%C; 8.04%H; 11.56%N.Found: 62.55%C; 7.94%H; 11.17%N.

EXAMPLE 233-[4-[1-(4-Fluorophenyl)-4-piperazinyl]butyl]-2-Methyl-4-thiazolidinonehydrochloride

To a solution of 2-methyl-3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and1-(4-fluorophenyl)piperazine (2.15 g) in 100 ml of anhydrous CH₃ CN wereadded K₂ CO₃ (3.5 g) and NaI (200 mg).

The mixture was heated to 80° with stirring under N₂. After 18 hours themixture was cooled to room temperature and filtered. The filtrate wasconcentrated in vacuo, and the residue was taken up in EtOAc andchromatographed (silica, EtOAc eluent). The fractions containing thedesired product were combined and concentrated.

The HCl salt was precipitated from Et₂ O, collected and dried to provide3.273 g of product as a white solid, mp 178°-182° (dec).

ANALYSIS: Calculated for C₁₈ H₂₄ FN₃ OS.HCl: 55.73%C; 7.01%H; 10.83%N.Found: 55.45%C; 6.90%H; 10.86%N.

EXAMPLE 243-[4-[1-(3-Chlorophenyl)-4-piperazinyl]butyl]-2-Methyl-4-thiazolidinonehydrochloride

To a solution of 2-methyl-3-(4-bromobutyl)-4-thiazolidinone (4.0 g) and1-(3-chlorophenyl)piperazine hydrochloride (3.69 g) in 100 ml of dry CH₃CN were added K₂ CO₃ (8.8 g) and NaI (200 mg). The mixture was heated toreflux with stirring under N₂.

After 18 hours the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc andchromatographed (silica, EtOAc as the eluent). The fractions containingthe desired product were combined and concentrated. The HCl salt of thefree amine was precipitated from Et₂ O and the excess HCl and Et₂ O wereremoved in vacuo to leave 5.176 g of product as a white solid, mp180°-183° (dec.)

ANALYSIS: Calculated for C₁₈ H₂₆ ClN₃ OS.HCl: 53.46%C; 6.73%H; 10.39%N.Found: 53.27%C; 6.88%H; 10.27%N.

EXAMPLE 253-[4-[1-(2-Methoxyphenyl)-4-piperazinyl]butyl]-5-methyl-4-thiazolidinoneoxalate

A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (5.03 g),1-(2-methoxyphenyl)piperazine (4.06 g), K₂ CO₃ (7.28 g), NaI (190 mg)and CH₃ CN (100 mL) was refluxed (bath temperature 99° C.) for 48 h. TLCanalysis (10% EtOH/CH₂ Cl₂) showed the absence of starting bromide andformation of one major product, R_(f) =0.48. The reaction mixture wascooled to room temperature and filtered, the filtrate was concentratedin vacuo and passed through silica gel to yield 6.06 g of an amber oil.Chromatography of the crude product, followed by treatment with etherealHCl yielded 5.45 g of a salt. Attempts to recrystallize the crude saltfailed, so it was freebased utilizing 5% NaHCO₃ yielding, after an EtOAcextraction, 3.82 g of an oil. The oil was chromatographed (silica gel,10% EtOH/CH₂ Cl₂) yielding 2.2 g of an oil which solidified on standing.The solid was rechromatographed (silica gel, 10% EtOH/CH₂ Cl₂) anddissolved in Et₂ O (200 ml), and its oxalate salt was precipitated bythe addition of a saturated solution of oxalic acid in Et₂ O. Theoxalate was dried in vacuo and recrystallized from EtOAc to yield finewhite needles, mp 129°-131° C.

ANALYSIS: Calculated for C₁₉ H₂₉ N₃ O₂ S.C₂ H₂ O₄ : 55.61%C; 6.89%H;9.26%N. Found: 55.56%C; 6.86%H; 9.33%N.

EXAMPLE 262,2-Dimethyl-3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonedihydrochloride

A mixture of 2,2-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.01 g),1-(3-methylphenyl)piperazine (3.17 g), K₂ CO₃ (5.30 g), NaI (230 mg) andCH₃ CN (180 mL) was heated at reflux (oil bath temperature; 100° C.) for20 h. TLC analysis (silica gel, 7.5% EtOH/CH₂ Cl₂ showed one majorproduct, R_(f) =0.53, and a trace of starting bromide, R_(f) =0.70. Thereaction mixture was cooled to room temperature, EtOAc (100 mL) wasadded and the mixture filtered. The filtrate was concentrated in vacuoto an oil which was triturated with EtOAc (150 mL). The mixture wasfiltered and the filtrate concentrated in vacuo to an oil. HPLC of thecrude oil (Waters Prep 500 silica gel, 8% MeOH/EtOAc) yielded 5.42 g ofan oil, R_(f) =0.53. The hydrochloride salt of this amine wasprecipitated by the addition of HCl/Et₂ O to a solution of the base in600 ml of ether until pH=2 to give 5.30 g of a white powder.Recrystallization from EtOH yielded 2.91 g of white crystals, mp 204° C.(dec).

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ OS.2HCl: 55.29%C; 7.66%H; 9.67%N;16.32%Cl. Found: 55.41%C; 8.07%C; 9.78%N; 16.65%Cl.

EXAMPLE 272,2-Dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride hydrate

To a solution of 2,2-dimethyl-3-(4-chlorobutyl)-4-thiazolidinone (3.26g) and 1-(2-methoxyphenyl)piperazine (2.8 g) in 100 ml of anhydrous CH₃CN were added anhydrous K₂ CO₃ (4.5 g) and NaI (200 mg). The mixture washeated with stirring to 80° under N₂.

After 18 hours the mixture was cooled to room temperature and filtered,concentrated in vacuo, taken up in EtOAc and again filtered. The EtOAcwas removed in vacuo and the residue chromatographed on silica usingEtOAc as the eluent to provide 4.2 g of amine.

The HCl salt was precipitated from Et₂ O and dried in vacuo to provide amonohydrate, homogeneous by TLC, mp 189°-192° C. The yield was 4.465 g.

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ O₂ S.HCl.H₂ O: 55.60%C; 7.93%H;9.72%N. Found: 55.28%C; 7.61%H; 9.53%N.

Karl Fisher Titration: Calculated: 4.17%. Found: 4.36%.

EXAMPLE 282,2-Dimethyl-3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinonedihydrochloride

A mixture of 2,2-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.02 g),1-(3-chlorophenyl)piperazine hydrochloride (3.85 g), K₂ CO₃ (6.84 g),NaI (200 mg) and CH₃ CN (160 mL) was refluxed (bath temperature 95° C.)under N₂ for 48 h. TLC analysis (silica gel, 7.5% EtOH/CH₂ Cl₂) showedone major product, R_(f) =0.33 and the absence of startingthiazolidinone. The mixture was cooled to room temperature, EtOAc (100ml) was added, and the mixture filtered. The filtrate was concentratedin vacuo to an oil which was redissolved in EtOAc causing a white solidto precipitate. The mixture was filtered and the filtrate concentratedin vacuo to an oil. Purification of the crude product by HPLC (WatersPrep 500 A, 5% EtOH/EtOAc) afforded 4.35 g of oil. The oil was dissolvedin Et₂ O (600 mL) and the solution acidified to pH=2 (hydrion paper)with an HCl/Et₂ O solution, and the precipitated salt (3.7 g) wasrecrystallized from EtOH to yield 2.10 g of a crystalline solid, mp205°-207° C.

ANALYSIS: Calculated for C₁₉ H₂₈ N₃ ClOS.2HCl: 50.16%C; 6.65%H; 9.24%N.Found: 50.23%C; 6.57%H; 9.19%N.

EXAMPLE 292,2-Dimethyl-3-[4-[1-(3-trifluoromethyl)-4-piperazinyl]butyl]-4-thiazolidinonedihydrochloride

A mixture of 2,2-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.06 g),1-(3-trifluoromethylphenyl)piperazine (4.07 g), K₂ CO₃ (5.11 g), NaI(200 mg) and CH₃ CN (160 mL) under N₂ was heated at reflux for 24 h. Thereaction mixture was cooled to room temperature and filtered, and thefiltrate concentrated in vacuo to an amber oil. The oil was trituratedwith EtOAc and the mixture was filtered. The filtrate was concentratedin vacuo to an oily residue which was chromatographed by HPLC (silicagel, 5% EtOH/EtOAc) to give 4.85 g of product which solidified oncooling. The solid was dissolved in Et₂ O (500 mL) and its HCl saltprecipitated by addition of HCl/Et₂ O. It was dried in vacuo andrecrystallized from isopropanol to yield white crystals, mp 184° C.(dec).

ANALYSIS: Calculated for C₂₀ H₃₀ F₃ Cl₂ N₃ OS.2HCl: 49.18%C; 6.19%H;8.60%N. Found: 49.24%C; 6.52%H; 8.84%N.

EXAMPLE 302,2-Dimethyl-3-[4-[1-(3-methylmercaptophenyl)-4-piperazinyl]butyl]-4-thiazolidinonedihydrochloride

A mixture of 2,2-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.17 g),1-(3-methylmercaptophenyl)piperazine (3.92 g), K₂ CO₃ (5.42 g), NaI (240mg) and CH₃ CN (180 mL) was heated to reflux (bath temperature 100° C.)under N₂ for 24 h. TLC analysis (silica gel, 5% EtOH/EtOAc) showed theabsence of starting bromide and the presence of one major product withR_(f) =0.23. The reaction mixture was cooled to room temperature, EtOAc(100 mL) was added, and the mixture filtered. The filtrate wasconcentrated in vacuo to an oil which was chromatographed by HPLC(silica gel, 8% MeOH/EtOAc) to give 5.60 g of a yellow oil. The oil wasdissolved in Et₂ O (450 mL) and the HCl salt of this amine wasprecipitated by the addition of an HCl/Et₂ O solution, yielding 6.26 gof a white solid. Recrystallization of the crude product from EtOH (250mL) and HCl/Et₂ O solution (2 mL) afforded 3.79 g of fine crystals, mp202° C. (dec).

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ OS₂.2HCl: 51.49%C; 7.13%H; 9.01%N.Found: 51.32%C; 7.42%H; 8.86%N.

EXAMPLE 315,5-Dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinonedihydrochloride

A mixture of 5,5-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.25 g),1-(2-methoxyphenyl)piperazine hydrochloride (4.38 g), K₂ CO₃ (8.8 g),NaI (300 mg) and acetonitrile (200 mL) was heated at 110° C. (bathtemperature) under nitrogen. After 25 hours, TLC analysis (silica gel,10% methanol/ethyl acetate) showed the absence of starting bromide and amajor product, R_(f) =0.20. The reaction mixture was cooled to roomtemperature, ethyl acetate (150 mL) was added, and the mixture filtered.The filtrate was concentrated in vacuo to an oil which was redissolvedin ethyl acetate causing a solid to precipitate. The mixture wasfiltered and the filtrate concentrated to 6.01 g of an oily residuewhich was chromatographed (Waters Prep 500, one silica gel column, 10%methanol/ethyl acetate) to give 3.02 g of an oil. Trituration of the oilwith diethyl ether (300 mL) deposited a fluffy white solid which wasremoved by filtration. The filtrate was acidified with an HCl/diethylether solution to pH=1 and the resulting salt (3.25 g) was collected asa white solid. After one recrystallization from EtOH/ethyl acetate thesalt was freebased to give 2.45 g of an oil which was dissolved indiethyl ether. The solution was filtered and the filtrate acidified withan HCl/diethyl ether solution again to yield 2.60 g of a salt.Recrystallization from EtOH/ether yielded 2.29 g of a white solid, mp213°-218° (dec.).

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ O₂ S.2HCl: 53.32%C; 7.38%H; 9.33%H;15.74%Cl. Found: 53.40%C; 7.46%H; 9.34%H; 15.76%Cl.

EXAMPLE 325,5-Dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

A mixture of 5,5-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(3-trifluoromethylphenyl)piperazine (4.15 g), K₂ CO₃ (6.22 g), NaI(220 mg) and CH₃ CN (120 mL) was refluxed (oil bath temperature=97° C.)under N₂ for 20 h. TLC analysis (silica gel, 10% MeOH/EtOAc) of thereaction mixture showed one major product, R_(f) =0.49, and the absenceof starting bromide. The mixture was cooled to room temperature, EtOAc(150 mL) was added, and the mixture filtered. The filtrate wasconcentrated in vacuo to a yellow oil. The oil was triturated with EtOAc(200 mL) and filtered, and the filtrate concentrated in vacuo to an oil.The crude oily product was chromatographed (Waters Prep 500, 2 silicagel columns, 5% MeOH/EtOAc) to give 4.2 g of a clear oil. The HCl saltof this amine was precipitated by the addition of a diethyl ether/HClsolution until pH=2 (hydrion paper). The resultant salt was collected,dried and recrystallized from ethanol/ethyl acetate to afford 2.85 g ofcrystals, mp 169°-171° C.

ANALYSIS: Calculated for C₂₀ H₂₈ F₃ N₃ OS.HCl: 53.15%C; 6.47%H; 7.84%N;9.30%Cl. Found: 53.10%C; 6.61%H; 8.09%N; 9.29%Cl.

EXAMPLE 335-Phenyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinoneoxalate

A mixture of 3-(4-bromobutyl)-5-phenyl-4-thiazolidinone (4.67 g),1-(3-trifluoromethylphenyl)piperazine (3.76 g), K₂ CO₃ (5.15 g), NaI(300 mg) and CH₃ CN (150 mL) was heated at reflux (bath temperature 95°C.) under N₂. After 17 hours, TLC analysis (silica gel, 5% MeOH/EtOAc)showed the absence of starting bromide and presence of one major productwith an R_(f) =0.33. The mixture was cooled to room temperature, EtOAc(100 mL) was added, and the mixture filtered. The filtrate wasconcentrated in vacuo to an oil which was triturated with EtOAc. Themixture was filtered and the filtrate concentrated again in vacuo to7.59 g of an oil. The crude product was chromatographed (Waters Prep500, 2 columns, silica gel, 5% MeOH/EtOAc) to give 6.42 g of an oil, andfrom this 4.47 g of the oxalate salt of this amine was prepared. Thesolid was recrystallized from EtOH/EtOAc giving 3.65 g of fine whitecrystals, mp 140°-142° C.

ANALYSIS: Calculated for C₂₄ H₂₈ F₃ N₃ OS.C₂ H₂ O₄ : 56.41%C; 5.46%H;7.59%N. Found: 56.31%C; 5.56%H; 7.53%N.

EXAMPLE 342-Methyl-3-[4-[1-(2-pyrimidyl)-4-piperazinyl]butyl]-4-thiazolidinonemaleate

To a stirred solution of 3-(4-bromobutyl)-2-methyl-4-thiazolidinone (3.0g) and 1-(2-pyrimidinyl)piperazine dihydrochloride (2.83 g) in 100 ml ofdry CH₃ CN were added K₂ CO₃ (6.6 g) and NaI (200 mg). The mixture washeated to reflux under N₂.

After 18 hours, the mixture was cooled to room temperature and filtered.The filtrate was concentrated in vacuo, taken up in EtOAc andchromatographed (silica, 10:90 CH₃ OH/EtOAc). The fractions containingthe desired product were combined and concentrated.

The maleate salt was precipitated from Et₂ O, collected and dried toprovide 3.18 g of product as a white solid, mp 155°-157° C., homogeneousby TLC (silica, 10:88:2 CH₂ OH/EtOAc/Et₃ N, R_(f) =0.26).

ANALYSIS: Calculated for C₁₆ H₂₅ N₅ OS.C₄ H₄ O₄ : 53.20%C; 6.47%H;15.51%N. Found: 53.00%C; 6.65%H; 15.43%N.

EXAMPLE 353-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (3.50 g),1-(1,2-benzisothiazol-3-yl)piperazine (3.87 g), K₂ CO₃ (6.09 g), NaI(200 mg) and acetonitrile (130 mL) was heated at reflux (bathtemperature 95° C.) under nitrogen. After 30 hours, TLC analysis (silicagel, 10% MeOH/EtOAc) showed the absence of the starting bromide and thepresence of a major product (R_(f) ≅0.21) and a minor product (R_(f)≅0.30). The reaction mixture was cooled to room temperature, ethylacetate (150 mL) was added and the mixture was filtered. The filtratewas concentrated in vacuo to a brown oil which was triturated withEtOAc. The mixture was filtered and the filtrate, after concentration invacuo, was chromatographed (Waters Prep 500, silica gel, 15% MeOH/EtOAc)to give 2.75 g of a yellowish oil.

The chromatographed free base (3.88 g) was dissolved in ethylacetate/diethyl ether, the resulting mixture was filtered in order toremove a fluffy insoluble material, and the filtrate was acidified withan HCl/diethyl ether solution until pH=1 (hydrion paper). The resultantsolid was collected and dried at 55° C./3.0 mmHg yielding 3.1 g of abeige solid, mp 219°-222° C. Recrystallization from EtOH (165 mL)yielded after drying (78° C./0.30 mmHg) 2.65 g of amber crystals, mp220°-225° C.

ANALYSIS: Calculated for C₁₈ H₂₄ N₄ OS₂.HCl: 52.35%C; 6.10%H; 13.57%N;8.58%Cl. Found: 52.10%C; 6.03%H; 13.41%N; 8.85%Cl.

EXAMPLE 363-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.50 g),1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.70 g), K₂ CO₃(6.34 g), NaI (330 mg) and acetonitrile (175 mL) was heated at 95° C.(bath temperature) under nitrogen. After 21 hours, TLC analysis (silicagel, 5% MeOH/CH₂ Cl₂) showed the absence of starting bromide and thepresence of a major product, R_(f) =0.33. The reaction mixture wascooled to room temperature, ethyl acetate (150 mL) was added, and themixture filtered. The filtrate was concentrated in vacuo to an oil whichwas triturated with ethyl acetate. The mixture was filtered again andthe filtrate, after concentration, was chromatographed (Waters Prep 500,one silica gel column, 3% MeOH/CH₂ Cl₂) to give 3.48 g of a viscous oil.The oil was dissolved in diethyl ether (500 mL), the solution filteredto remove a fluffy solid, and the filtrate acidified to pH=1 (hydrionpaper) with an HCl/diethyl ether solution. The resultant salt (3.23 g)was recrystallized from ethanol/ethyl acetate yielding 2.29 g of whiteneedles, mp 222°-227° C.

ANALYSIS: Calculated for C₂₀ H₂₈ N₄ OS₂.HCl: 54.46%C; 6.63%H; 12.70%N;8.04%Cl. Found: 53.93%C; 6.73%H; 12.58%N; 8.57%Cl.

EXAMPLE 373-[4-[1-(2-Benzothiazolyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.42 g),1-(2-benzothiazolyl)piperazine (3.10 g), K₂ CO₃ (6.19 g), NaI (250 mg)and acetonitrile was heated at 65° C. (bath temperature) under nitrogen.After 19 hours, TLC analysis (5% methanol/methylene chloride) showed theabsence of starting bromide and the presence of a major product, R_(f)=0.29. The reaction mixture was cooled to room temperature, ethylacetate (100 ml) was added and the mixture filtered. The filtrate wasconcentrated in vacuo to a solid which was redissolved in hot ethylacetate causing a solid to precipitate. The mixture was filtered and thefiltrate concentrated in vacuo to an off-white solid. Chromatography ofthe crude product by HPLC (Waters Prep 500, one silica gel column, 5%methanol/methylene chloride) yielded 4.05 g of a solid, mp 99.5°-100.5°C. It was recrystallized from methylene chloride/hexane to give 2.83 gof fine needles, mp 101°-102° C.

ANALYSIS: Calculated for C₂₀ H₂₈ N₄ OS₂ : 59.37%C; 6.98%H; 13.85%N.Found: 59.29%C; 7.06%H; 14.01%N.

EXAMPLE 38 3-[4-[1-(2-Quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(2-quinolinyl)piperazine (3.94 g), K₂ CO₃ (6.97 g), NaI (230 mg) andacetonitrile (150 mL) was heated at 80° C. (bath temperature) undernitrogen. After 19 hours, TLC analysis (silica gel, 13% MeOH/EtOAc)showed the absence of starting bromide and the presence of one majorproduct, R_(f) =0.19. The reaction mixture was cooled to roomtemperature, ethyl acetate (100 mL) was added, and the mixture wasfiltered. The filtrate was concentrated in vacuo to a solid andtriturated with EtOAc. The mixture was filtered again to removeinsoluble materials and the filtrate concentrated in vacuo to 6.32 g ofbeige solid. Chromatography of the crude product by HPLC (Waters Prep500, one silica gel column 8% MeOH/CH₂ Cl₂) yielded 5.67 g of a solid,mp 105°-107° C. It was recrystallized from ethyl acetate/cyclohexane togive 3.62 g of off-white crystals, mp 106°-107.5° C.

ANALYSIS: Calculated for C₂₀ H₂₆ N₄ OS: 64.83%C; 7.07%H; 15.12%N. Found:64.78%C; 7.07%H; 15.18%N.

EXAMPLE 395,5-Dimethyl-3-[4-[1-(2-quinolinyl)-4-piperazinyl]butyl]-4-thiazolidinone

A mixture of 5,5-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.20 g),1-(2-quinolinyl)piperazine (3.70 g), K₂ CO₃ (6.55 g), NaI (200 mg) andacetonitrile (150 mL) was heated at reflux (bath temperature 95° C.)under N₂ for 20 h. TLC analysis (silica gel, 10% MeOH/EtOAc) showed theabsence of starting bromide and the formation of a major product, R_(f)=0.31. The reaction mixture was cooled to room temperature and leftstanding for 44 h. To this was added ethyl acetate (100 ml) and theresultant mixture was filtered. The filtrate was concentrated in vacuoto an oily solid which was redissolved in ethyl acetate (200 mL) causinga white solid to precipitate. The mixture was gravity filtered and thefiltrate concentrated to an off-white solid (6.86 g). Chromatography ofthe crude product (Waters Prep 500, 1 silica gel column, 10% MeOH/EtOAc)yielded 4.22 g of a white solid (R_(f) =0.26), mp 107°-111° C. It wasrecrystallized from ethyl acetate/hexane (1:2) to yield 2.83 g of whitecrystals, mp 110.5°-111.5° C.

ANALYSIS: Calculated for C₂₂ H₃₀ N₄ OS: 66.29%C; 7.59%H; 14.06%N. Found:66.26%C; 7.61%H; 13.95%N.

EXAMPLE 403-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,2-dimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(1,2-benzisothiazol-3-yl)piperazine (3.62 g), K₂ CO₃ (7.25 g), NaI(400 mg) and CH₃ CN (180 mL) was heated at 80° C. under nitrogen. After20 h, TLC analysis (silica gel, 5% MeOH/CH₂ Cl₂) showed the absence ofstarting bromide and the presence of a major product, R_(f) =0.40. Themixture was cooled to room temperature, EtOAc (100 mL) was added, andthe mixture filtered. The filtrate was concentrated in vacuo to an oilwhich was dissolved in EtOAc (150 mL) causing a small amount of solid toprecipitate. The mixture was filtered again and the filtrateconcentrated to a yellowish brown oil. The oil was chromatographed(Waters Prep 500, 1 silica gel column, 4% MeOH/CH₂ Cl₂) to yield 5.10 gof a yellowish solid.

The solid (5.00 g) was dissolved in EtOAc (100 mL)/Et₂ O (500 mL) andthe resultant cloudy solution was filtered to remove a small amount ofbrown solid. The filtrate was acidified with an HCl/Et₂ O solution untilpH=2. The resultant salt was collected and dried to give 5.15 g of anoff-white powder, mp 211°-214° C. A 4.00 g sample of the salt wasrecrystallized from EtOH/ethyl acetate to yield 2.92 g of white needles,mp 213°-216° C.

ANALYSIS: Calculated for C₂₀ H₂₈ N₄ OS₂.HCl: 54.46%C; 6.63%H; 12.70%N;8.04%Cl. Found: 54.16%C; 6.66%H; 12.58%N; 8.10%Cl.

EXAMPLE 413-[4-[1-(2-Benzothiazolyl)-4-piperazinyl]butyl]-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(2-benzothiazolyl)piperazine (4.05 g), K₂ CO₃ (7.01 g), NaI (250 mg)and acetonitrile (160 mL) was heated at 93° (bath temperature) undernitrogen. After 19 h, TLC analysis (silica gel, 5% methanol/methylenechloride) showed the absence of starting bromide and the presence of amajor product, R_(f) =0.26. The reaction mixture was cooled to roomtemperature, ethyl acetate (100 mL) was added, and the mixture filtered.The filtrate was concentrated in vacuo to a solid which was redissolvedin ethyl acetate causing a white solid to precipitate. The mixture wasfiltered again and the filtrate concentrated in vacuo to 6.43 g of anoff-white solid. Chromatography of the crude product by HPLC (WatersPrep 500, 1 silica gel column, 5% methanol/methylene chloride) yielded5.44 g of an off-white solid. A sample of the solid (3.08 g) wasrecrystallized from methylene chloride (15 mL)/hexanes (85 mL) yielding2.28 g of a crystalline solid, mp 111°-112° C.

ANALYSIS: Calculated for C₁₈ H₂₄ N₄ OS₂ : 57.42%C; 6.42%H; 14.88%N.Found: 57.36%C; 6.38%H; 14.83%N.

EXAMPLE 423-[4-[1-(3-Isoquinolinyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g),1-(3-isoquinolinyl)piperazine (3.53 g), K₂ CO₃ (6.22 g), NaI (300 mg)and acetonitrile (190 mL) was heated at 75° C. (bath temperature) underN₂. After 16 h, TLC analysis (silica gel, 40% EtOAc/hexane) showed theabsence of starting bromide and a major product at R_(f) =0.22 (silicagel, 5% MeOH/CH₂ Cl₂). The reaction mixture was cooled to ambienttemperature and filtered, the inorganic solid was washed with hot ethylacetate, and the wash was combined with the above filtrate andconcentrated in vacuo to a green solid. The solid was triturated withhot ethyl acetate (300 mL) and the mixture filtered. The filtrate wasconcentrated in vacuo to a solid which was chromatographed (Waters Prep500, 1 silica gel column, 5% MeOH/CH₂ Cl₂) to yield 5.10 g of a greensolid. The solid was recrystallized from methylene chloride/hexanes togive 2.99 g of light green crystals, mp 145°-146.5° C.

ANALYSIS: Calculated for C₂₂ H₃₀ N₄ OS: 66.29%C; 7.59%H; 14.06%N. Found:66.45%C; 7.60%H; 14.00%N.

EXAMPLE 43 3-(4-Bromobutyl)-2,2,5,5-tetramethyl-4-thiazolidinone

To a -75° C. solution of 3-(4-bromobutyl)-2,2-dimethyl-4-thiazolidinone(13.18 g), iodomethane (22.83 g) and THF (30 ml) was added a -75° C.solution of lithium bis(trimethylsilyl)amide (0.100 mol) in THF (110 ml)over a period of 12 minutes. The resulting solution was stirred at -75°C. for 25 minutes, removed from the cold bath and acidified with 1N HCl(250 ml). The aqueous mixture was extracted with diethylether (3×125ml). The combined extracts were washed with brine (150 ml), dried(anhydrous Na₂ SO₄) and concentrated under reduced pressure to give16.86 g of liquid. Column chromatography of the liquid using silica gel(about 600 g) and elution with 30% ethyl acetate/hexanes afforded 12.50g of oil.

Molecular distillation of 2.5 g of the oil (0.10 mmHg/92°-100° C. bathtemperature) yielded 2.1 g of a colorless oil which solidified oncooling, m.p. 30°-31° C.

ANALYSIS: Calculated for C₁₁ H₂₀ BrNOS: 44.90%C; 6.85%H; 4.76%N. Found:44.65%C; 6.92%H; 4.67%N.

EXAMPLE 44 2-Methyl-3-(4-bromobutyl)-1-thia-3-aza[4.4]nonan-4-one

To a solution prepared from 2-methyl-3-(4-bromobutyl)-4-thiazolidinone(8.00 g), 1,4-diiodobutane (11 ml) and THF (75 ml) and maintained at-60° C. was added dropwise under nitrogen a solution of lithiumbis(trimethylsilyl)amide (0.066 mole) in THF (66 ml) during which thetemperature was maintained below -54° C. The addition was completewithin 20 minutes. The reaction mixture was stirred for additional 30minutes, the cold bath was removed, the mixture was warmed to 5° C. andit was quenched with 200 ml of 0.66N HCl solution. The resultant mixturewas placed under vacuum to remove the THF and extracted with ether(3×100 ml). The ether extract was washed successively with water (150ml) and brine (150 ml) and thereafter dried (Na₂ SO₄) and concentratedto yield a viscous liquid. The oil was chromatographed on silica gel(500 g) using 30-50% ethyl acetate/hexane as eluent to obtain 6.38 g ofliquid.

EXAMPLE 45 3-(4-Bromobutyl)-1-thia-3-azaspiro[5.4]decan-4-one

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in THF (350ml) cooled to -60° C. was added 1,5-diiodopentane (100 g), and theresultant slurry was cooled to -65° C. A solution of lithiumbis(trimethylsilyl)amide (0.220 mole) in hexanes (220 ml) was addeddropwise, during which the internal temperature was maintained at orbelow -55° C. The addition was complete within 30 minutes. The mixturewas stirred for additional 15 minutes at the same temperature andthereafter warmed to 0° C. with the aid of an ice bath. The mixture wasstirred for additional 20 minutes and thereafter quenched with 500 ml of0.5N HCl solution. The resultant mixture was placed under vacuum toremove some of the THF and thereafter extracted with ether (350 ml,2×250 ml). The combined extracts were washed successively with water(400 ml) and brine (400 ml), dried with Na₂ SO₄ and concentrated to aliquid. The liquid was chromatographed (2 silica gel columns) using20-60% ethyl acetate/hexane as an eluent to obtain about 20.5 g of solidproduct.

EXAMPLE 46 3-(4-Bromobutyl)-5-(2-hydroxyisopropyl)-4-thiazolidinone

To a solution of 3-(4-bromobutyl)-4-thiazolidinone (10.0 g) intetrahydrofuran (200 ml) cooled to -78° C. under nitrogen was addedrapidly a solution of lithium bis(trimethylsilyl)amide (0.044 mol) intetrahydrofuran (44 ml) followed immediately by acetone (10 ml). Theresulting solution was stirred at -78° C. for 20 minutes, the cold bathwas removed and 0.5N HCl (250 ml) was added. The aqueous mixture wasplaced under reduced pressure to remove some of the tetrahydrofuran. Theresulting mixture was extracted with ether (3×125 ml). The combinedextracts were washed with brine (200 ml), dried (Na₂ SO₄) andconcentrated to a viscous liquid. The liquid was chromatographed onsilica gel (400 g) eluting with 50-100% ethyl acetate/hexanes to afford8.96 g of oil. The oil was dried at 0.2 mmHg for 48 hours.

ANALYSIS: Calculated for C₁₀ H₁₈ BrNO₂ S: 40.55%C; 6.12%H; 4.73%N.Found: 40.20%C; 6.17%H; 4.67%N.

EXAMPLE 47 3-(4-Bromobutyl)-5-(2-fluoroisopropyl)-4-thiazolidinone

To a -67° C. solution of dimethylaminosulfur trifluoride (3.15 g) anddichloromethane (100 ml) under nitrogen was added a solution of3-(4-bromobutyl)-5-(2-hydroxyisopropyl)-4-thiazolidinone (7.01 g) anddichloromethane (30 ml) dropwise over a period of 35 minutes. Theresulting solution was allowed to warm to ambient temperature over aperiod of 80 minutes. Cold water (75 ml) was added and the layers wereseparated. The organic layer was washed successively with water (75 ml)and brine (100 ml), dried (NaSO₄) and concentrated to a liquid. Theliquid was purified by chromatography on silica gel (350 g) eluting with40-60% ethyl acetate/hexanes to give 6.01 g oil. A 2.07 g sample of oilwas distilled using a molecular still (120° C./0.20 mmHg) to give 1.75 gof a clear liquid.

ANALYSIS: Calculated for C₁₀ H₁₇ BrFNOS: 40.28%C; 5.75%H; 4.70%N. Found:40.39%C; 5.82%H; 4.56%N.

EXAMPLE 483-[4-[1-(2-Methylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (4.00 g),1-(2-methylphenyl)-piperazine (3.87 g), K₂ CO₃ (8.31 g), NaI (290 mg)and acetonitrile (175 ml) was heated at 75° C. (bath temperature) undernitrogen. After 16 hours, TLC analysis (silica gel, 5% MeOH/CH₂ Cl₂)showed absence of the starting bromide and presence of a major product,R_(f) =0.24. The reaction mixture was cooled to room temperature, ethylacetate (150 ml) was added, and the mixture filtered. The filtrate wasconcentrated in vacuo to an oil which was dissolved into ethyl acetatecausing a solid to precipitate. The mixture was filtered and thefiltrate concentrated in vacuo to 6.35 g of an oil. The oil waschromatographed (5% MeOH/CH₂ Cl₂, one silica gel column) to obtain 4.91g of a solid. The solid was dissolved in diethylether (550 ml), thesolution filtered to remove a trace of insoluble material, and thefiltrate acidified to pH=1 with a HCl/diethylether solution. Theresulting salt was collected and dried to give 4.83 g of powder. Thepowder was recrystallized twice from ethanol/ethyl acetate to yield 2.14g of crystals, m.p. 230°-235° C.

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ OS.HCl: 60.35%C; 8.11%H; 10.56%N;8.91%Cl. Found: 60.27%C; 8.27%H; 10.52%N; 9.02%Cl.

EXAMPLE 493-[4-[1-(2,3-Dimethylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinonehydrochloride

A mixture of 1-(2,3-dimethylphenyl)piperazine (3.56 g),3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.80 g), K₂ CO₃ (7.90g), NaI (380 mg) and CH₃ CN (210 ml) was heated at 80° C. (oil bathtemperature) under nitrogen. After 17 hours, the mixture was cooled toambient temperature, EtOAc (125 ml) was added, and the inorganicsfiltered. The filtrate was concentrated under reduced pressure to give5.59 g of viscous liquid. The crude product was purified by preparativeHPLC on silica gel eluting with 5% MeOH/CH₂ Cl₂ to yield 3.80 g ofsolid, m.p. 100°-104° C., R_(f) =0.43. The HCl salt of this amine wasprepared to afford 3.58 g of powder. Recrystallization of the salt fromCH₂ Cl₂ /EtOAc gave 2.43 g of fine needles, m.p. 248°-256° C.

ANALYSIS: Calculated for C₂₁ H₃₃ N₃ OS.HCl: 61.21%C; 8.32%H; 10.20%N;8.60%Cl. Found: 60.85%C; 8.33%H; 10.12%N; 8.91%Cl.

EXAMPLE 503-[4-[1-(3-Phenyl-1H-indolyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (2.3 g),1-phenyl-3-piperazino-1H-indole (2.17 g), K₂ CO₃ (2.2 g), NaI (200 mg)and 150 ml anhydrous CH₃ CN was heated to 80° C. with stirring under N₂.After 18 hours no starting material remained as judged by TLC. Themixture was cooled to room temperature, filtered and the filtrateconcentrated in vacuo. The residue was chromatographed on silica usingEtOAc as an eluent. The fractions containing the desired product werecombined, concentrated and taken up in Et₂ O. The HCl salt of the aminewas precipitated by the addition of HCl in Et₂ O, and recrystallizedfrom Et₂ O/CH₂ Cl₂ to provide 1.349 g of product as bis-salt, m.p.205°-208° C., homogeneous by TLC.

ANALYSIS: Calculated for C₂₇ H₃₄ N₄ OS.2HCl: 60.55%C; 6.78%H; 10.46%N.Found: 60.94%C; 6.41%H; 10.40%N.

EXAMPLE 513-[4-[1-[1-(4-Fluorophenyl)-1H-indol-3-yl]-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-4-thiazolidinone (3.2 g),1-(4-fluorophenyl)-3-piperazino-1H-indole (3.6 g), K₂ CO₃ (3.4 g), NaI(200 mg) and 150 ml anhydrous CH₃ CN was heated to 80° C. with stirringunder N₂. After 18 hours no starting material remained as judged by TLC.The mixture was cooled to room temperature and filtered, and thefiltrate concentrated in vacuo. The residue was chromatographed onsilica using EtOAc as an eluent. The fractions containing the desiredproduct were combined and concentrated in vacuo and taken up in Et₂ O.The bis-HCl salt of the amine was precipitated by the addition of HCl inEt₂ O, and recrystallized from hexane/Et₂ O/CH₂ Cl₂ to provide 3.363 gof product as the bis-salt, m.p. 195°-198° C., homogeneous by TLC.

ANALYSIS: Calculated for C₂₇ H₃₃ FN₄ OS.2HCl: 58.57%C; 6.37%H; 10.12%N.Found: 58.32%C; 6.45%H; 10.14%N.

EXAMPLE 523-[4-[1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,2,5,5-tetramethyl-4-thiazolidinonehydrochloride hemihydrate

A mixture of 3-(4-bromobutyl)-2,2,5,5-tetramethyl-4-thiazolidinone (4.00g), 1-(1,2-benzisothiazol-3-yl)-piperazine hydrochloride (3.82 g), K₂CO₃ (6.58 g), NaI (300 mg) and acetonitrile (190 ml) was heated at 80°C. (oil bath temperature) under nitrogen. After 14 hours, TLC analysis(silica 25% EtOAc/hexane) showed the starting bromide to be absent,R_(f) =0.39. The reaction mixture was cooled to room temperature, ethylacetate (100 ml) was added, and the mixture filtered. The filtrate wasconcentrated in vacuo to an oil. The oil was dissolved in ethyl acetatecausing a solid to precipitate. The resulting mixture was filtered andthe filtrate concentrated in vacuo to 6.65 g of oil which was purifiedby HPLC (silica gel 4% methanol/methylene chloride) to give 5.20 g of anoil (R_(f) =0.29 major and R_(f) =0.36 trace, 3% MeOH/CH₂ Cl₂, twoelutions).

The oil was dissolved in ethyl acetate/diethylether and the solutionacidified with a HCl/diethylether solution until pH=2. The resultingsalt was collected and dried to give 5.00 g of powder. The powder wasrecrystallized twice from ethanol/ethyl acetate yielding 2.65 g of fineneedles, m.p. 218°-221° C.

ANALYSIS: Calculated for C₂₂ H₃₂ N₄ OS₂.HCl.0.5H₂ O: 55.27%C; 7.17%H;11.72%N; 7.42%Cl. Found: 55.31%C; 7.28%H; 11.65%N; 7.73%Cl.

EXAMPLE 533-[4-[1-(Benzo[b]thiophen-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-onemaleate

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (3.70g), 3-piperazinyl benzo[b]thiophene (3.10 g), K₂ CO₃ (7.00 g), NaI (300mg) and acetonitrile (220 ml) was stirred at 35° C. under nitrogen.After 18 hours, TLC analysis showed the starting biomide (R_(f) =0.46:silica gel, 40% ethyl acetate/hexanes) to be absent. The mixture wascooled to ambient temperature, ethyl acetate (150 ml) was added, theinorganics filtered, and the filtrate concentrated under reducedpressure. The residue was taken up in dichloromethane (220 ml), washedsuccessively with H₂ O (110 ml) and brine (130 ml), dried (Na₂ SO₄) andconcentrated to a foam. The foam was chromatographed on silica gel (450g), eluting with 5% methanol in dichloromethane, to afford 3.62 g of afoam (R_(f) =0.31, 5% methanol/dichloromethane) which solidified uponaddition of ether. The solid (mp: 99°-102° C.) was dissolved in ethanol(40 ml)/ether (230 ml) and the solution acidified by the addition of asaturated maleic acid/ether solution. The resulting salt (4.01 g) wasrecrystallized from ethanol/ethyl acetate to yield 2.83 g of powder,m.p. 177°-180° C.

ANALYSIS: Calculated for C₂₇ H₃₅ N₃ O₅ S₂ : 59.43%C; 6.46%H; 7.70%N.Found: 59.33%C; 6.41%H; 7.67%N.

EXAMPLE 543-[4-[1-(1-Phenyl-1H-indol-3-yl)-4-piperazinyl]butyl]-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-onedihydrochloride

A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one(6.80 g), 1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (4.80 g),diisopropylethyl amine (8.16 g), K₂ CO₃ (9.50 g), NaI (400 mg) and CH₃CN (200 ml) was heated at 80° C. under nitrogen for 24 hours. Themixture was cooled and filtered, the inorganics were washed withdichloromethane, and the filtrate was concentrated under reducedpressure to a residue. The residue was diluted with 0.5N NaOH (150 ml)and the aqueous mixture extracted with ether (3×100 ml). The combinedether extracts were washed successively with H₂ O (150 ml) and brine(150 ml), dried (Na₂ SO₄), and concentrated in vacuo. The crude productwas chromatographed on silica gel, eluting with a gradient of 5-10%methanol in dichloromethane. The fractions containing the desiredproduct (R_(f) =0.42, 10% methanol in dichloromethane) were concentratedto afford 4.84 g of a viscous liquid. The salt of this amine wasprecipitated from ether by the addition of ethereal HCl. A 4.74 gportion of the salt was recrystallized from ethanol yielding 2.15 g ofsolid, m.p. 214°-217° C.

ANALYSIS: Calculated for C₃₀ H₃₈ N₄ OS.2HCl: 62.60%C; 7.00%H; 9.73%N.Found: 62.58%C; 6.95%H; 9.69%N.

EXAMPLE 553-[4-[1-(Benzo[b]thiophen-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.5]decan-4-onemaleate

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one (4.47g), 3-piperazinylbenzo[b]thiophene (3.50 g), K₂ CO₃ (6.67 g), NaI (300mg) and acetonitrile (210 ml) was heated at 70° C. under nitrogen. After17 hours, TLC analysis showed a trace of the starting bromide (R_(f)=0.41, 40% ethyl acetate/hexanes, silica gel). The mixture was cooled toambient temperature, ethyl acetate (150 ml) was added, the inorganicsfiltered, and the filtrate concentrated under reduced pressure. Theresidue was taken up in dichloromethane (220 ml), washed successivelywith H₂ O (140 ml) and brine (150 ml), dried (Na₂ SO₄), and concentratedto a viscous liquid. The liquid was chromatographed on silica gel,eluting with 5% methanol in dichloromethane, to afford 4.50 g of viscousliquid (R_(f) =0.33, 5% methanol/dichloromethane, silica gel). Theliquid was dissolved in ether and the solution acidified with asaturated maleic acid/ether solution to give 5.00 g of a salt. The saltwas recrystallized from ethanol/ethyl acetate yielding 3.58 g of afluffy solid, m.p. 191°-192° C. (dec.).

ANALYSIS: Calculated for C₂₄ H₃₃ N₃ OS₂.C₄ H₄ O₄ : 60.08%C; 6.66%H;7.51%N. Found: 59.96%C; 6.57%H; 7.51%N.

EXAMPLE 563-[4-[1-(1-Phenyl-1H-indol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[5.4]decan-4-onedihydrochloride

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[5.4]decan-4-one (4.00g), 1-(1-phenyl-1H-indol-3-yl)piperazine (1.20 g), K₂ CO₃ (6.50 g), NaI(300 mg) and acetonitrile (330 ml) was heated under nitrogen at 80° C.After 38 hours the mixture was cooled to ambient temperature andfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was taken up in dichloromethane, washed successively with H₂ O(150 ml) and brine (150 ml), dried (Na₂ SO₄), and concentrated to aliquid. The liquid was chromatographed on silica gel, eluting with 5 to10% methanol in dichloromethane, affording 2.73 g of liquid. The liquidwas dissolved in ethanol and the salt of the amine precipitated by theaddition of ethereal HCl to afford 1.90 g of solid. Recrystallizationfrom ethanol gave 1.13 g of powder, m.p. 158° C. (begin decomposition).

ANALYSIS: Calculated for C₃₀ H₃₈ N₄ OS.2HCl: 62.60%C; 7.00%H; 9.73%N.Found: 62.36%C; 6.86%H; 9.70%N.

EXAMPLE 573-[4-[1-[1-(4-Fluorophenyl)-1H-indol-3-yl]-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.5]decan-4-one

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one (3.8 g),1-(4-fluorophenyl)-3-piperazino-1H-indole (3.7 g), K₂ CO₃ (3.5 g), NaI(200 mg) and anhydrous CH₃ CN (150 ml) was heated to 80° C. withstirring under nitrogen. After 18 hours, no starting amine remained asjudged by TLC. The mixture was cooled to room temperature and filtered,and the filtrate concentrated in vacuo. The residue was chromatographedon silica using EtOAc as an eluent. The fractions containing the desiredproduct were combined and concentrated to provide 2.816 g of crystals,m.p. 134°-136° C., homogeneous by TLC.

ANALYSIS: Calculated for C₃₀ H₃₇ FN₄ OS: 69.20%C; 7.16%H; 10.76%N.Found: 69.09%C; 7.14%H; 10.62%N.

EXAMPLE 58 3-(4-Bromobutyl)-5-methyl-4-thiazolidinone

As an alternative to the method described in Example 7, the titlecompound was prepared in the following manner:

To a -74° C. solution of 3-(4-bromobutyl)-4-thiazolidinone (5.20 g) andTHF (70 ml) under nitrogen was rapidly added lithiumbis(trimethylsilyl)amide (0.023 mole) in THF (23 ml) followedimmediately by methyliodide (7.74 g). The resulting solution was stirredfor 20 minutes (cooled by the CO₂ /isopropanol bath), allowed to warm to-40° C., and acidified with 1N HCl (200 ml). The resulting aqueousmixture was extracted with 25% benzene/ether (3×100 ml). The combinedextracts were washed with brine (200 ml), dried (Na₂ SO₄), andconcentrated in vacuo to a liquid which was chromatographed on silicagel, eluting with 45% ethyl acetate in hexanes, yielding 3.84 g of anoil. The oil was distilled to give 2.60 g of a colorless liquid, b.p.123°-125° C. at 0.20 mmHg.

ANALYSIS: Calculated for C₈ H₁₄ BrNOS: 38.10%C; 5.60%H; 5.55%N. Found:38.12%C; 5.58%H; 5.48%N.

EXAMPLE 593-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl-5-(2-hydroxyisopropyl)-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-5-(2-hydroxyisopropyl)-4-thiazolidinone(4.00 g), 3-piperazinyl-1,2-benzisothiazol hydrochloride (3.80 g), K₂CO₃ (8.00 g), NaI (450 mg), and acetonitrile (200 ml) was heated at 80°C. under nitrogen. After 17 hours the mixture was filtered, theinsolubles were washed with dichloromethane, and the filtrate wasconcentrated in vacuo. The residue was taken up in dichloromethane (200ml), washed successively with 5% NaOH (100 ml) and H₂ O (100 ml), anddried. Evaporation of the solvent at reduced pressure gave a viscousliquid. The crude product was chromatographed on silica gel. Elutionwith 8% methanol in dichloromethane gave 5.06 g of liquid. The HCl saltof this amine was prepared and recrystallized from ethanol/ethyl acetateto afford 2.26 g of a fine crystalline solid, m.p. 147°-150°.

ANALYSIS: Calculated for C₂₀ H₃₀ N₄ O₂ S₂.HCl: 53.54%C; 6.63%H; 11.89%N.Found: 53.31%C; 6.53%H; 11.80%N.

EXAMPLE 603-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butylspiro[1H-indene-2,5-thiazolidine]-2,3-dihydro-4-one

A mixture of3-(4-bromobutyl)-spiro[1H-indene-2,5-thiazolidine]-2,3-dihydro-4-one(4.00 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.31 g),K₂ CO₃ (7.20 g), NaI (350 mg), and acetonitrile was heated at 80° C.under nitrogen. After 17 hours, the mixture was filtered, the insolubleswashed with dichloromethane (120 ml), and the filtrate concentratedunder reduced pressure. The residue was taken up in dichloromethane (225ml), washed successively with 0.5 on NaOH (125 ml), H₂ O (125 ml) andbrine (125 ml), and thereafter dried (Na₂ SO₄), and concentrated to afoam. The foam was purified by repeated chromatography on silica gel,eluting with 8% methanol in dichloromethane, to give 3.50 g of solid.The HCl salt of this amine was prepared and recrystallized repeatedlyfrom ethanol/ethyl acetate to affor 1.03 g of solid, m.p. 192°-195° C.

ANALYSIS: Calculated for C₂₆ H₃₀ N₄ OS₂.HCl: 60.62%C; 6.07%H; 10.88%N.Found: 60.05%C; 6.13%H; 10.69%N.

EXAMPLE 613-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4-thiazolidinone

A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.00 g),1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.46 g), K₂ CO₃(8.00 g) and NaI (300 mg) in acetonitrile (210 ml) was heated at 40°-45°C. for 64 hours and the product was processed in substantially the samemanner as in Example 10 to afford 3.64 g of crystals, m.p. 113°-115° C.

ANALYSIS: Calculated for C₁₉ H₂₆ N₄ OS₂ : 58.43%C; 6.71%H; 14.34%N.Found: 58.32%C; 6.69%H; 14.29%N.

EXAMPLE 623-(4-(1-(6-Fluorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-5-(2-hydroxyisopropyl)-4-thiazolidinonemaleate

A mixture of 3-(4-bromobutyl)-5-(2-hydroxyisopropyl)-4-thiazolidinone(5.00 g), 1-(6-fluorobenzo[b]thiophen-3-yl)piperazine (4.44 g), K₂ CO₃(8.20 g) and NaI (400 mg) in acetonitrile (200 ml) was heated at 75° C.for 16 hours and the product was processed in substantially the samemanner as in Example 10 to afford 2.35 g of crystalline solid, m.p.159°-161° C.

ANALYSIS: Calculated for C₂₂ H₃₀ FN₃ O₂ S₂.C₄ H₄ O₄ : 55.01%C; 6.04%H;7.40%N. Found: 54.92%C; 5.99%H; 7.41%N.

EXAMPLE 633-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone(3.20 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (2.81 g),K₂ CO₃ (4.83 g) and NaI (250 mg) in acetonitrile (280 ml) was heated at70° C. for 15 hours and the product was processed in substantially thesame manner as in Example 10 to afford 2.30 g of crystals, m.p.188°-200° C.

ANALYSIS: Calculated for C₂₀ H₂₅ F₃ N₄ OS₂.HCl: 48.52%C; 5.29%H;11.32%N; 7.16%Cl. Found: 48.51%C; 5.32%H; 11.20%N; 7.28%Cl.

EXAMPLE 643-(4-(1-(3-Methylphenyl)-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (4.00 g),1-(3-methylphenyl)piperazine (3.43 g), K₂ CO₃ (8.31 g) and NaI (270 mg)in acetonitrile (180 ml) was heated at 75° C. for 17 hours and theproduct was processed in substantially the same manner as in Example 10to afford 2.10 g of needles, m.p. 145° C. (begin decomposition).

ANALYSIS: Calculated for C₂₀ H₃₁ N₃ OS.2HCl: 55.29%C; 7.66%H; 9.67%N;16.32%Cl. Found: 55.06%C; 7.68%H; 9.62%N; 16.29%Cl.

EXAMPLE 653-(4-(1-(6-Fluorobenzo[b]thiophen-3-yl)piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinonemaleate

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.00 g),1-(6-fluorobenzo[b]thiophen-3-yl)piperazine (3.71 g), K₂ CO₃ (6.00 g)and NaI (400 mg) in acetonitrile was heated at 50° C. for 16 hours andthe product was processed in substantially the same manner as in Example10 to afford 2.09 g of solid, m.p. 170°-174° C.

ANALYSIS: Calculated for C₂₂ H₃₀ N₃ FOS₂.C₄ H₄ O₄ : 56.60%C; 6.21%H;7.62%N. Found: 56.57%C; 6.24%H; 7.62%N.

EXAMPLE 663-(4-(1-(6-Chlorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g),6-chloro-3-piperazinylbenzo[b]thiophene (5.41 g), K₂ CO₃ (8.63 g) andNaI (400 mg) in acetonitrile (200 ml) was heated at 90° C. for 16.5hours and the product was processed in substantially the same manner asin Example 10 to afford 2.25 g of powder, m.p. 199°-202° C.

ANALYSIS: Calculated for C₂₂ H₃₀ ClN₃ OS₂ HCl: 54.09%C; 6.40%H; 8.60%N.Found: 53.67%C; 6.31%H; 8.60%N.

EXAMPLE 673-(4-(1-[1-Phenyl-1H-indol-3-yl]-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g),1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (7.80 g),N,N-diisopropylethylamine (9.65 g), NaI (350 mg) in acetonitrile (250ml) was heated at 75° C. for 17 hours and the product was processed insubstantially the same manner as in Example 10 to afford 2.80 g ofcrystals, m.p. 217°-219° C.

ANALYSIS: Calculated for C₂₈ H₃₆ N₄ OS.2HCl: 61.19%C; 6.97%H; 10.19%N.Found: 61.11%C; 6.91%H; 10.18%N.

EXAMPLE 683-(4-(1-(1-(4-Fluorophenyl)-1H-indol-3-yl)-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinonedihydrochloride hemihydrate

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.46 g),1-(4-fluorophenyl)-3-piperazino-1H-indole (4.7 g), K₂ CO₃ (4.4 g) andNaI (200 mg) in acetonitrile (175 ml) was heated at 80° C. for 18 hoursand the product was processed in substantially the same manner as inExample 10 to afford 3.29 g of product, m.p. 182°-185° C.

ANALYSIS: Calculated for C₂₈ H₃₅ FN₄ OS-2HCl-0.5H₂ O: 58.32%C; 6.64%H;9.71%N. Found: 58.11%C; 6.35%H; 9.72%N.

EXAMPLE 693-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)-2,5,5-trimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.70 g),1-(1,2-benzisothiazol-3-yl)piperazine1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.72 g), K₂ CO₃(8.13 g) and NaI (300 mg) in acetonitrile (200 ml) was heated at 65° C.for 16 hours and the product was processed in substantially the samemanner as in Example 10 to afford 2.77 g of crystals, m.p. 209°-214° C.

ANALYSIS: Calculated for C₂₁ H₃₀ N₄ OS₂.HCl: 55.43%C; 6.87%H; 12.31%N;7.79%Cl. Found: 55.26%C; 6.82%H; 12.30%N; 7.97%Cl.

EXAMPLE 703-[4-[1-(6-Chloro-1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidinonehydrochloride

A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (3.6 g),6-chloro-1,2-benzisothiazol-3-yl piperazine (3.7 g), K₂ CO₃ (4.0 g) andNaI (200 mg) in CH₃ CN (175 ml) was heated at 80° C. for 18 hours andthe product was processed in substantially the same manner as in Example10 to afford 4.714 g of product, m.p. 204°-206° C.

ANALYSIS: Calculated for C₂₁ H₂₉ N₄ OS₂.HCl: 51.53%C; 6.18%H; 11.44%N.Found: 51.45%C; 6.12%H; 11.48%N.

EXAMPLE 713-(4-(1-[3-methylphenyl]-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-2,2,5,5-tetramethyl-4-thiazolidinone (3.80g), 1-(3-methylphenyl)piperazine (2.60 g), K₂ CO₃ (6.42 g) and NaI (400mg) in acetonitrile (200 ml) was heated at 80° C. for 16 hours and theproduct was processed in substantially the same manner as in Example 10to afford 2.96 g of needles, m.p. 182° C. (begin decomposition).

ANALYSIS: Calculated for C₂₂ H₃₅ N₃ OS.2HCl: 57.13%C; 8.06%H; 9.08%N;15.33%Cl. Found: 56.92%C; 8.00%H; 8.93%N; 15.38%Cl.

EXAMPLE 723-(4-(1-(2-Methoxyphenyl)-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinonedihydrochloride

A mixture of 3-(4-bromobutyl)-2,2,5,5-tetramethyl-4-thiazolidinone (3.60g), 1-(2-methoxyphenyl)piperazine (2.59 g), K₂ CO₃ (5.90 g) and NaI (320mg) in acetonitrile (190 ml) was heated at 90° C. for 14 hours and theproduct was processed in substantially the same manner as in Example 10to afford 2.43 g of solid, m.p. 138° C. (being decomposition).

ANALYSIS: Calculated for C₂₂ H₃₇ Cl₂ N₃ O₂ S: 55.22%C; 7.79%H; 8.78%N;14.82%Cl. Found: 54.98%C; 7.69%H; 8.75%N; 14.95%Cl.

EXAMPLE 733-(4-(1-(2-Methoxyphenyl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-onedihydrochloride

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.60g), 1-(2-methoxyphenyl)piperazine (3.33 g), K₂ CO₃ (5.42 g) and NaI (310mg) in acetonitrile (200 ml) was heated at 65° C. for 6 hours and theproduct was processed in substantially the same manner as in Example 10to afford 3.43 g of crystals, m.p. 144° C. (begin decomposition).

ANALYSIS: Calculated for C₂₂ H₃₃ N₃ O₂ S.2HCl: 55.45%C; 7.40%H; 8.82%N;14.88%Cl. Found: 55.54%C; 7.40%H; 8.80%N; 14.54%Cl.

EXAMPLE 743-(4-(1-(Benzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-onemaleate

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (3.70g), 3-piperazinyl benzo[b]thiophene (3.10 g), K₂ CO₃ (7.00 g) and NaI(300 mg) in acetonitrile (220 ml) was heated at 35° C. for 18 hours andthe product was processed in substantially the same manner as in Example10 to afford 2.83 g of powder, m.p. 177°-180° C.

ANALYSIS: Calculated for C₂₇ H₃₅ N₃ O₅ S₂ : 59.43%C; 6.46%H; 7.70%N.Found: 59.33%C; 6.41%H; 7.67%N.

EXAMPLE 753-[4-[1-(1,2-Benzisothioazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.4]nonan-4-one

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.33 g), K₂ CO₃(7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65° C.for 14.5 hours and the product was processed in substantially the samemanner as in Example 10 to afford 2.25 g of crystals, m.p. 200°-203° C.

ANALYSIS: Calculated for C₂₂ H₃₀ N₄ OS₂.HCl: 56.57%C; 6.69%H; 11.99%N;7.59%Cl. Found: 56.15%C; 6.75%H; 12.11%N; 7.88%Cl.

EXAMPLE 763-(4-(1-(1,1-dioxo-1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-one

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (3.50g), 1-(1,1-dioxo-1,2-benzisothiazol-3-yl)piperazine (3.30 g), K₂ CO₃(4.98 g) and NaI (280 mg) in acetonitrile (230 ml) was heated at 85° C.for 20 hours and the product was processed in substantially the samemanner as in Example 10 to afford 2.89 g of needles, m.p. 137°-140° C.

ANALYSIS: Calculated for C₂₂ H₃₀ N₄ O₃ S₂ : 57.12%C; 6.54%H; 12.11%N.Found: 57.24%C; 6.57%H; 12.12%N.

EXAMPLE 773-(4-(1-(6-Fluorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2-methyl-3-azaspiro[4.4]nonan-4-onemaleate

A mixture of 3-(4-bromobutyl)-2-methyl-3-azaspiro[4.4]-nonan-4-one (5.00g), 6-fluoro-3-piperazinyl-benzo[b]thiophene (4.55 g), K₂ CO₃ (8.00 g)and NaI (0.400 mg) in acetonitrile was heated at 80° C. for 2.5 hoursand the product was processed in substantially the same manner as inExample 10 to afford 4.38 g of solid, m.p. 174°-176° C.

ANALYSIS: Calculated for C₂₄ H₃₂ FN₃ OS₂.C₄ H₄ O₄ : 58.21%C; 6.28%H;7.27%N. Found: 57.93%C; 6.20%H; 7.23%N.

EXAMPLE 783-(4-(1-(6-Chlorobenzo[b]thiophen-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-onehydrochloride

A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one(5.00 g), 6-chloro-3-piperazinylbenzo[b]thiophene (5.10 g), K₂ CO₃ (8.00g) and NaI (400 mg) in acetonitrile (250 ml) was heated at 85° C. for15.5 hours and the product was processed in substantially the samemanner as in Example 10 to afford 1.43 g of crystalline solid, m.p.211°-214° C.

ANALYSIS: Calculated for C₂₄ H₃₂ ClN₃ OS₂.HCl: 56.02%C; 6.46%H; 8.17%N.Found: 55.81%C; 6.50%H; 8.24%N.

EXAMPLE 793-(4-(1-(1,2-Benzisothiazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-onehydrochloride

A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one(3.84 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.49 g),K₂ CO₃ (5.90 g) and NaI (280 mg) in acetonitrile (215 ml) was heated atbetween 65°-80° C. for 16.5 hours and the product was processed insubstantially the same manner as in Example 10 to afford 2.86 g ofcrystals, m.p. 210°-215° C.

ANALYSIS: Calculated for C₂₃ H₃₂ N₄ OS₂.HCl: 57.42%C; 6.91%H; 11.64%N;7.37%Cl. Found: 57.21%C; 6.87%H; 11.63%N; 7.03%Cl.

EXAMPLE 803-(4-(1-[1,2-Benzisothiazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan-4-one

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.00g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.67 g), K₂ CO₃(7.00 g) and NaI (300 mg) in acetonitrile (220 ml) was heated at 70° C.for 20 hours and the product was processed in substantially the samemanner as in Example 10 to afford 3.01 g of crystalline solid, m.p. 209°C.

ANALYSIS: Calculated for C₂₃ H₃₂ N₄ OS₂.HCl: 57.42%C; 6.91%H; 11.64%N;7.37%Cl. Found: 57.51%C; 6.82%H; 11.75%N; 7.30%Cl.

EXAMPLE 813-[4-[1-(6-Chloro-1,2-benzisothiazol-3-yl)-4-piperazinyl]butyl]-1-thia-3-azaspiro[4.5]decan-4-onehydrochloride

A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decanone (2.7 g),6-chloro-1,2-benzisothiazol-3-yl piperazine (2.0 g), K₂ CO₃ (2.2 g) andNaI (200 mg) in acetonitrile (100 ml) was heated at 80° C. for 8 hoursand the product was processed in substantially the same manner as inExample 10 to afford 1.557 g of solid, m.p. 202°-205° C.

ANALYSIS: Calculated for C₂₃ H₃₁ N₄ OS₂ Cl.HCl: 53.58%C; 6.26%H;10.87%N. Found: 53.54%C; 6.20%H; 10.85%N.

EXAMPLE 82 3-(4-Bromobutyl)-2,5,5-trimethyl-4-thiazolidinone

To a -73° C. solution of 3-(4-bromobutyl)-2-methyl-4-thiazolidinone(6.00 g), methyliodide (10.99 g) and THF (50 ml) under nitrogen wasadded lithium bis(trimethylsilyl)amide (0.0500 mol) in THF (50 ml) at arate to maintain the internal temperature below -55° C. The resultingsolution was stirred at <-55° C. for 10 minutes, allowed to warm to -40°C., and at which temperature 1N HCl (250 ml) was added. The aqueousmixture was extracted with 25% benzene/ether (3×125 ml). The combinedextracts were washed with brine (200 ml), dried (Na₂ SO₄), andconcentrated to a liquid which was chromatographed on silica gelyielding 5.07 g of a liquid. The liquid was distilled to give 3.80 g ofa clear liquid, b.p. 109°-114° C. at 0.20 mmHg.

ANALYSIS: Calculated for C₁₀ H₁₈ BrNOS: 42.86%C; 6.47%H; 5.00%N. Found:42.93%C; 6.47%H; 5.00%N.

We claim:
 1. A compound of the formula ##STR21## where n is 0 or 1; A is##STR22## where X in each occurrence is independently hydrogen, halogen,loweralkyl, hydroxy, nitro, loweralkoxy, amino, cyano, trifluoromethylor methylthio; m is 1 or 2; R₁ and R₂ are independently hydrogen,loweralkyl, ##STR23## or aryl except that when R₁ is ##STR24## or aryl,R₂ is hydrogen, or alternatively R₁ +R₂ taken together with the carbonatom to which they are attached form a cyclopentane, cyclohexane,cycloheptane, pyran, thiopyran, indan or piperidine ring; R₃ and R₄ areindependently hydrogen or loweralkyl, or alternatively R₃ +R₄ takentogether with the carbon atom to which they are attached form acyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, pyrrolidineor piperidine ring, the term aryl signifying an unsubstituted phenylgroup or a phenyl group substituted with 1, 2 or 3 substituents each ofwhich being independently loweralkyl, loweralkoxy, hydroxy, halogen,loweralkythio, cyano, amino or trifluoromethyl, or a pharmaceuticallyacceptable acid addition salt thereof.
 2. The compound according toclaim 1, where n=0.
 3. The compound according to claim 1, where R₁ =R₂=H.
 4. The compound according to claim 1, where R₁ +R₂ =--(CH₂)₄ --. 5.The compound according to claim 1, where R₁ =R₂ =CH₃.
 6. The compoundaccording to claim 1, where ##STR25## where P is hydrogen, loweralkyl,loweralkoxy, hydroxy, loweralkylthio or amino and R₂ is hydrogen.
 7. Thecompound according to claim 1, where R₃ and R₄ are independentlyhydrogen or loweralkyl.
 8. The compound according to claim 2, where R₁=R₂ =H.
 9. The compound according to claim 2, where R₁ +R₂ =--(CH₂)₄ --.10. The compound according to claim 2, where R₁ =R₂ =CH₃.
 11. Thecompound according to claim 2, where ##STR26## where P is hydrogen,loweralkyl, loweralkoxy, hydroxy, loweralkylthio or amino and R₂ ishydrogen.
 12. The compound according to claim 2, where R₃ and R₄ areindependently hydrogen or loweralkyl.
 13. The compound according toclaim 1, which is3-[4-[1-(2-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 14. Thecompound according to claim 1, which is3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 15. Thecompound according to claim 1, which is3-[4-[1-(2,3-dimethylphenyl)-4-piperazinyl]butyl]-4≢-thiazolidinone. 16.The compound according to claim 1, which is3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 17. Thecompound according to claim 1, which is3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 18. Thecompound according to claim 1, which is3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 19. Thecompound according to claim 1, which is3-[4-[1-(2-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 20. Thecompound according to claim 1, which is3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 21. Thecompound according to claim 1, which is3-[4-[1-(4-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.
 22. Thecompound according to claim 1, which is3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.23. The compound according to claim 1, which is3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidine.24. The compound according to claim 1, which is3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-1,4-dioxothiazolidinone.25. The compound according to claim 1, which is3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone.26. The compound according to claim 1, which is3-[4-[1-(4-fluorophenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone.27. The compound according to claim 1, which is3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-2-methyl-4-thiazolidinone.28. The compound according to claim 1, which is3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-5-methyl-4-thiazolidinone.29. The compound according to claim 1, which is2,2-dimethyl-3-[4-[1-(3-methylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.30. The compound according to claim 1, which is2,2-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.31. The compound according to claim 1, which is2,2-dimethyl-3-[4-[1-(3-chlorophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.32. The compound according to claim 1, which is2,2-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.33. The compound according to claim 1, which is2,2-dimethyl-3-[4-[1-(3-methylthiophenyl)-4-piperazinyl]butyl]-4-thiazolidinone.34. The compound according to claim 1, which is5,5-dimethyl-3-[4-[1-(2-methoxyphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.35. The compound according to claim 1, which is5,5-dimethyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.36. The compound according to claim 1, which is5-phenyl-3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-4-thiazolidinone.37. The compound according to claim 1, which is3-[4-[1-(3-trifluoromethylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone.38. The compound according to claim 1, which is3-[4-[1-(2-methylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone.39. The compound according to claim 1, which is3-[4-[1-(2,3-dimethylphenyl)-4-piperazinyl]butyl]-5,5-dimethyl-4-thiazolidinone.40. The compound according to claim 1, which is3-(4-(1-(3-methylphenyl)-4-piperazinyl)butyl)-5,5-dimethyl-4-thiazolidinone.41. The compound according to claim 1, which is3-(4-(1-[3-methylphenyl]-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinone.42. The compound according to claim 1, which is3-(4-(1-(2-methoxyphenyl)-4-piperazinyl)butyl)-2,2,5,5-tetramethyl-4-thiazolidinone.43. The compound according to claim 1, which is3-(4-(1-(2-methoxyphenyl)-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan-4-one.